Methods for treating huntington&#39;s disease

ABSTRACT

In particular, the present description relates to substituted monocyclic heteroaryl compounds of Formula (I), forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington&#39;s disease.

The present description relates to compounds, forms, and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease. In particular, the present description relates to substituted monocyclic heteroaryl compounds, forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease.

BACKGROUND

Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder of the brain, having symptoms characterized by involuntary movements, cognitive impairment, and mental deterioration. Death, typically caused by pneumonia or coronary artery disease, usually occurs 13 to 15 years after the onset of symptoms. The prevalence of HD is between three and seven individuals per 100,000 in populations of western European descent. In North America, an estimated 30,000 people have HD, while an additional 200,000 people are at risk of inheriting the disease from an affected parent. The disease is caused by an expansion of uninterrupted trinucleotide CAG repeats in the “mutant” huntingtin (Htt) gene, leading to production of HTT (Htt protein) with an expanded poly-glutamine (polyQ) stretch, also known as a “CAG repeat” sequence. There are no current small molecule therapies targeting the underlying cause of the disease, leaving a high unmet need for medications that can be used for treating or ameliorating HD. Consequently, there remains a need to identify and provide small molecule compounds for treating or ameliorating HD.

All other documents referred to herein are incorporated by reference into the present application as though fully set forth herein.

SUMMARY

The present description relates to methods for treating or ameliorating HD in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I):

wherein W, X, A and B are as defined herein, or forms and compositions thereof.

In particular, the present description relates to a use of a compound of Formula (I) or a form or composition thereof in a method for treating or ameliorating HD in a subject in need thereof comprising, administering an effective amount of the compound or a form or composition thereof, to the subject.

The present description further relates to the use of a compound of Formula (I) or a form thereof in combination with agents having additive or synergistic activity, thus providing a combination product for the treatment of HD.

DETAILED DESCRIPTION

The present description relates to a method or use of a compound for treating or ameliorating HD in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I):

-   or a form thereof, wherein -   W is CH═CH or S; -   X is CH₂, CH(C₁₋₄alkyl), C(C₁₋₄alkyl)₂, CH═CH, O, NR₅, or a bond; -   A is aryl, heteroaryl, heterocyclyl, or C₉₋₁₀cycloalkyl, -   wherein aryl is selected from phenyl and naphthyl, each optionally     substituted with 1, 2, 3, or 4 substituents each selected from R₁, -   wherein heteroaryl is a monocyclic, bicyclic or polycyclic aromatic     carbon atom ring structure radical in which one or more carbon atom     ring members have been replaced, where allowed by structural     stability, with one or more heteroatoms, such as an O, S, or N atom,     each optionally substituted with 1, 2, 3, 4, or 5 substituents each     selected from R₁, -   wherein heterocyclyl is a saturated or partially unsaturated     monocyclic, bicyclic or tricyclic ring system having 1, 2, or 3     heteroatom ring members independently selected from N, O, or S, each     optionally substituted with 1, 2, 3, 4, or 5 substituents each     selected from R₂, and -   wherein C₉₋₁₀cycloalkyl is a saturated or partially unsaturated     bicyclic ring system optionally substituted with 1, 2, 3, 4, or 5     substituents each selected from R₂; -   B is heterocyclyl, -   wherein heterocyclyl is a saturated or partially unsaturated     monocyclic, bicyclic or polycyclic ring system having 1, 2, or 3     heteroatom ring members independently selected from N, O, or S, each     optionally substituted with 1, 2, 3, 4, or 5 substituents each     selected from R₄; -   R₁ is halogen, hydroxyl, cyano, C₁₋₄alkyl, halo-C₁₋₄alkyl, amino,     C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, amino-C₁₋₄alkyl,     C₁₋₄alkyl-amino-C₁₋₄alkyl, (C₁₋₄alkyl)₂-amino-C₁₋₄alkyl,     amino-carbonyl, C₁₋₄alkyl-amino-carbonyl,     (C₁₋₄alkyl)₂-amino-carbonyl, C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl,     (C₁₋₄alkyl)₂-amino-carbonyl-C₁₋₄alkyl, C₁₋₄alkyl-carbonyl-amino,     C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl, hydroxyl-C₁₋₄alkyl,     C₁₋₄alkyl-carbonyl, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, amino-C₁₋₄alkoxy,     hydroxyl-C₁₋₄alkoxy, C₁₋₄alkyl-C₁₋₄alkoxy,     C₁₋₄alkyl-amino-C₁₋₄alkoxy, (C₁₋₄alkyl)₂-amino-C₁₋₄alkoxy,     C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄alkoxy,     C₁₋₄alkoxy-carbonyl, C₁₋₄alkoxy-carbonyl-amino,     C₁₋₄alkoxy-carbonyl-amino-C₁₋₄alkoxy, C₂₋₄alkenyl,     C₂₋₄alkenyl-amino-carbonyl, C₃₋₇cycloalkyl,     C₃₋₇cycloalkyl-C₁₋₄alkoxy, C₃₋₇cycloalkenyl, heteroaryl,     heteroaryl-C₁₋₄alkyl, heteroaryl-C₁₋₄alkyl-amino,     heteroaryl-C₁₋₄alkyl-amino-carbonyl,     heteroaryl-C₁₋₄alkyl-carbonyl-amino,     heteroaryl-C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl,     heteroaryl-C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl, heterocyclyl,     heterocyclyl-C₁₋₄alkyl, heterocyclyl-C₁₋₄alkoxy, phenyl, or     phenyl-C₁₋₄alkoxy, -   wherein heteroaryl is a monocyclic, bicyclic or polycyclic aromatic     carbon atom ring structure radical in which one or more carbon atom     ring members have been replaced, where allowed by structural     stability, with one or more heteroatoms such as an O, S, or N atom, -   wherein heterocyclyl is a saturated or partially unsaturated     monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring     members selected from N, O, and S, and -   wherein each instance of phenyl, heteroaryl or heterocyclyl is     optionally substituted with 1, or 2 substituents each selected from     R₃; -   R₂ is halogen, hydroxyl, cyano, oxo, hydroxyl-imino, C₁₋₄alkyl,     halo-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino,     amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl,     (C₁₋₄alkyl)₂-amino-C₁₋₄alkyl, amino-carbonyl, hydroxyl-C₁₋₄alkyl,     C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl, C₂₋₄alkenyl, C₃₋₇cycloalkyl, or     heterocyclyl-C₁₋₄alkyl, -   wherein heterocyclyl is a saturated or partially unsaturated     monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring     members selected from N, O, and S, and -   wherein each instance of heterocyclyl is optionally substituted with     1, or 2 substituents each selected from R₃; -   R₃ is halogen, hydroxyl, nitro, oxo, hydroxyl-imino, C₁₋₄alkyl,     halo-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino,     amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl,     (C₁₋₄alkyl)₂-amino-C₁₋₄alkyl, amino-carbonyl,     C₁₋₄alkyl-amino-carbonyl, (C₁₋₄alkyl)₂-amino-carbonyl,     C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl,     (C₁₋₄alkyl)₂-amino-carbonyl-C₁₋₄alkyl, C₁₋₄alkyl-carbonyl-amino,     C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl, hydroxyl-C₁₋₄alkyl,     C₁₋₄alkyl-carbonyl, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, amino-C₁₋₄alkoxy,     hydroxyl-C₁₋₄alkoxy, C₁₋₄alkyl-C₁₋₄alkoxy,     C₁₋₄alkyl-amino-C₁₋₄alkoxy, (C₁₋₄alkyl)₂-amino-C₁₋₄alkoxy,     C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄alkoxy,     C₁₋₄alkoxy-carbonyl, C₁₋₄alkoxy-carbonyl-amino,     C₁₋₄alkoxy-carbonyl-amino-C₁₋₄alkoxy, C₂₋₄alkenyl,     C₂₋₄alkenyl-amino-carbonyl, C₃₋₇cycloalkyl,     C₃₋₇cycloalkyl-C₁₋₄alkoxy, C₃₋₇cycloalkenyl, heteroaryl,     heteroaryl-C₁₋₄alkyl, heteroaryl-C₁₋₄alkyl-amino,     heteroaryl-C₁₋₄alkyl-amino-carbonyl,     heteroaryl-C₁₋₄alkyl-carbonyl-amino,     heteroaryl-C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl,     heteroaryl-C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl, heterocyclyl,     heterocyclyl-C₁₋₄alkyl, phenyl, or phenyl-C₁₋₄alkoxy; -   R₄ is independently selected from halogen, C₁₋₄alkyl,     hydroxyl-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino or     hydroxyl-C₁₋₄alkyl-amino; and -   R₅ is hydrogen, C₁₋₄alkyl, or hydroxyl-C₁₋₄alkyl; -   wherein a form of the compound is selected from the group consisting     of a prodrug, salt, hydrate, solvate, clathrate, isotopologue,     racemate, enantiomer, diastereomer, stereoisomer, polymorph and     tautomer form thereof.

An embodiment of the present description further relates to a method or use of a compound for treating or ameliorating HD in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) selected from a compound of Formula (Ia) and Formula (Ib):

-   or a form thereof, wherein -   X is CH₂, CH(C₁₋₄alkyl), C(C₁₋₄alkyl)₂, CH═CH, O, NR₅, or a bond; -   A is aryl, heteroaryl, heterocyclyl, or C₉₋₁₀cycloalkyl, -   wherein aryl is selected from phenyl and naphthyl, each optionally     substituted with 1, 2, 3, or 4 substituents each selected from R₁, -   wherein heteroaryl is a monocyclic, bicyclic or polycyclic aromatic     carbon atom ring structure radical in which one or more carbon atom     ring members have been replaced, where allowed by structural     stability, with one or more heteroatoms, such as an O, S, or N atom,     each optionally substituted with 1, 2, 3, 4, or 5 substituents each     selected from R₁, -   wherein heterocyclyl is a saturated or partially unsaturated     monocyclic, bicyclic or tricyclic ring system having 1, 2, or 3     heteroatom ring members independently selected from N, O, or S, each     optionally substituted with 1, 2, 3, 4, or 5 substituents each     selected from R₂, and -   wherein C₉₋₁₀cycloalkyl is a saturated or partially unsaturated     bicyclic ring system optionally substituted with 1, 2, 3, 4, or 5     substituents each selected from R₂; -   B is heterocyclyl, -   wherein heterocyclyl is a saturated or partially unsaturated     monocyclic, bicyclic or polycyclic ring system having 1, 2, or 3     heteroatom ring members independently selected from N, O, or S, each     optionally substituted with 1, 2, 3, 4, or 5 substituents each     selected from R₄; -   R₁ is halogen, hydroxyl, cyano, C₁₋₄alkyl, halo-C₁₋₄alkyl, amino,     C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, amino-C₁₋₄alkyl,     C₁₋₄alkyl-amino-C₁₋₄alkyl, (C₁₋₄alkyl)₂-amino-C₁₋₄alkyl,     amino-carbonyl, C₁₋₄alkyl-amino-carbonyl,     C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl, C₁₋₄alkyl-carbonyl-amino,     C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl, hydroxyl-C₁₋₄alkyl,     C₁₋₄alkyl-carbonyl, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, amino-C₁₋₄alkoxy,     hydroxyl-C₁₋₄alkoxy, C₁₋₄alkyl-C₁₋₄alkoxy,     C₁₋₄alkyl-amino-C₁₋₄alkoxy, (C₁₋₄alkyl)₂-amino-C₁₋₄alkoxy,     C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄alkoxy,     C₁₋₄alkoxy-carbonyl, C₁₋₄alkoxy-carbonyl-amino,     C₁₋₄alkoxy-carbonyl-amino-C₁₋₄alkoxy, C₂₋₄alkenyl,     C₂₋₄alkenyl-amino-carbonyl, C₃₋₇cycloalkyl,     C₃₋₇cycloalkyl-C₁₋₄alkoxy, C₃₋₇cycloalkenyl, heteroaryl,     heteroaryl-C₁₋₄alkyl, heteroaryl-C₁₋₄alkyl-amino,     heteroaryl-C₁₋₄alkyl-amino-carbonyl,     heteroaryl-C₁₋₄alkyl-carbonyl-amino,     heteroaryl-C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl,     heteroaryl-C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl, heterocyclyl,     heterocyclyl-C₁₋₄alkyl, heterocyclyl-C₁₋₄alkoxy, phenyl, or     phenyl-C₁₋₄alkoxy, -   wherein heteroaryl is a monocyclic, bicyclic or polycyclic aromatic     carbon atom ring structure radical in which one or more carbon atom     ring members have been replaced, where allowed by structural     stability, with one or more heteroatoms such as an O, S, or N atom, -   wherein heterocyclyl is a saturated or partially unsaturated     monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring     members selected from N, O, and S, and -   wherein each instance of phenyl, heteroaryl or heterocyclyl is     optionally substituted with 1, or 2 substituents each selected from     R₃; -   R₂ is halogen, hydroxyl, cyano, oxo, hydroxyl-imino, C₁₋₄alkyl,     halo-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino,     amino-C₁₋₄alkyl, amino-carbonyl, hydroxyl-C₁₋₄alkyl, C₁₋₄alkoxy,     C₁₋₄alkoxy-carbonyl, C₂₋₄alkenyl, C₃₋₇cycloalkyl, or     heterocyclyl-C₁₋₄alkyl; -   R₃ is halogen, hydroxyl, nitro, oxo, hydroxyl-imino, C₁₋₄alkyl,     amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, amino-C₁₋₄alkyl,     C₁₋₄alkyl-amino-C₁₋₄alkyl, (C₁₋₄alkyl)₂-amino-C₁₋₄alkyl,     amino-carbonyl, C₁₋₄alkyl-amino-carbonyl,     C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl, C₁₋₄alkyl-carbonyl-amino,     C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl, hydroxyl-C₁₋₄alkyl,     C₁₋₄alkyl-carbonyl, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, amino-C₁₋₄alkoxy,     hydroxyl-C₁₋₄alkoxy, C₁₋₄alkyl-C₁₋₄alkoxy,     C₁₋₄alkyl-amino-C₁₋₄alkoxy, (C₁₋₄alkyl)₂-amino-C₁₋₄alkoxy,     C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄alkoxy,     C₁₋₄alkoxy-carbonyl, C₁₋₄alkoxy-carbonyl-amino,     C₁₋₄alkoxy-carbonyl-amino-C₁₋₄alkoxy, C₂₋₄alkenyl,     C₂₋₄alkenyl-amino-carbonyl, C₃₋₇cycloalkyl,     C₃₋₇cycloalkyl-C₁₋₄alkoxy, C₃₋₇cycloalkenyl, heteroaryl,     heteroaryl-C₁₋₄alkyl, heteroaryl-C₁₋₄alkyl-amino,     heteroaryl-C₁₋₄alkyl-amino-carbonyl,     heteroaryl-C₁₋₄alkyl-carbonyl-amino,     heteroaryl-C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl,     heteroaryl-C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl, heterocyclyl,     heterocyclyl-C₁₋₄alkyl, phenyl, or phenyl-C₁₋₄alkoxy; -   R₄ is independently selected from halogen, C₁₋₄alkyl,     hydroxyl-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino or     hydroxyl-C₁₋₄alkyl-amino; and -   R₅ is hydrogen, C₁₋₄alkyl, or hydroxyl-C₁₋₄alkyl; -   wherein a form of the compound is selected from the group consisting     of a prodrug, salt, hydrate, solvate, clathrate, isotopologue,     racemate, enantiomer, diastereomer, stereoisomer, polymorph and     tautomer form thereof.

Another embodiment of the present description further relates to methods for treating or ameliorating HD in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) selected from a compound of Formula (Ia) and Formula (Ib):

or a form thereof, wherein X is O, NH, N(CH₃) or a bond; A is aryl, heteroaryl or heterocyclyl, wherein aryl is selected from the group consisting of

wherein heteroaryl is selected from the group consisting of

wherein heterocyclyl is selected from the group consisting of

B is heterocyclyl selected from the group consisting of

-   R_(1a), R_(1b) and R_(1c) are each, where allowed by available     valences, one or more substituents each selected from halogen,     hydroxyl, cyano, C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino,     (C₁₋₄alkyl)₂-amino, amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl,     (C₁₋₄alkyl)₂-amino-C₁₋₄alkyl, amino-carbonyl,     C₁₋₄alkyl-amino-carbonyl, (C₁₋₄alkyl)₂-amino-carbonyl,     C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl,     (C₁₋₄alkyl)₂-amino-carbonyl-C₁₋₄alkyl, C₁₋₄alkyl-carbonyl-amino,     C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl, hydroxyl-C₁₋₄alkyl,     C₁₋₄alkyl-carbonyl, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, amino-C₁₋₄alkoxy,     hydroxyl-C₁₋₄alkoxy, C₁₋₄alkyl-C₁₋₄alkoxy,     C₁₋₄alkyl-amino-C₁₋₄alkoxy, (C₁₋₄alkyl)₂-amino-C₁₋₄alkoxy,     C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄alkoxy,     C₁₋₄alkoxy-carbonyl, C₁₋₄alkoxy-carbonyl-amino,     C₁₋₄alkoxy-carbonyl-amino-C₁₋₄alkoxy, C₂₋₄alkenyl,     C₂₋₄alkenyl-amino-carbonyl, C₃₋₇cycloalkyl,     C₃₋₇cycloalkyl-C₁₋₄alkoxy, C₃₋₇cycloalkenyl, heteroaryl,     heteroaryl-C₁₋₄alkyl, heteroaryl-C₁₋₄alkyl-amino,     heteroaryl-C₁₋₄alkyl-amino-carbonyl,     heteroaryl-C₁₋₄alkyl-carbonyl-amino,     heteroaryl-C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl,     heteroaryl-C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl, heterocyclyl,     heterocyclyl-C₁₋₄alkyl, heterocyclyl-C₁₋₄alkoxy, phenyl, or     phenyl-C₁₋₄alkoxy, -   wherein heteroaryl is a monocyclic, bicyclic or polycyclic aromatic     carbon atom ring structure radical in which one or more carbon atom     ring members have been replaced, where allowed by structural     stability, with one or more heteroatoms such as an O, S, or N atom, -   wherein heterocyclyl is a saturated or partially unsaturated     monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring     members selected from N, O, and S, and -   wherein each instance of phenyl, heteroaryl or heterocyclyl is     optionally substituted with 1, or 2 substituents each selected from     R₃; -   R_(2a), R_(2b) and R_(2c) are each, where allowed by available     valences, one or more substituents each selected from halogen,     hydroxyl, cyano, oxo, hydroxyl-imino, C₁₋₄alkyl, halo-C₁₋₄alkyl,     amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, amino-C₁₋₄alkyl,     C₁₋₄alkyl-amino-C₁₋₄alkyl, (C₁₋₄alkyl)₂-amino-C₁₋₄alkyl,     amino-carbonyl, hydroxyl-C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy-carbonyl,     C₂₋₄alkenyl, C₃₋₇cycloalkyl, or heterocyclyl-C₁₋₄alkyl, -   wherein heterocyclyl is a saturated or partially unsaturated     monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring     members selected from N, O, and S, and -   wherein each instance of heterocyclyl is optionally substituted with     1, or 2 substituents each selected from R₃; -   R₃ is halogen, hydroxyl, nitro, oxo, hydroxyl-imino, C₁₋₄alkyl,     amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, amino-C₁₋₄alkyl,     C₁₋₄alkyl-amino-C₁₋₄alkyl, (C₁₋₄alkyl)₂-amino-C₁₋₄alkyl,     amino-carbonyl, C₁₋₄alkyl-amino-carbonyl,     (C₁₋₄alkyl)₂-amino-carbonyl, C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl,     (C₁₋₄alkyl)₂-amino-carbonyl-C₁₋₄alkyl, C₁₋₄alkyl-carbonyl-amino,     C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl, hydroxyl-C₁₋₄alkyl,     C₁₋₄alkyl-carbonyl, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, amino-C₁₋₄alkoxy,     hydroxyl-C₁₋₄alkoxy, C₁₋₄alkyl-C₁₋₄alkoxy,     C₁₋₄alkyl-amino-C₁₋₄alkoxy, (C₁₋₄alkyl)₂-amino-C₁₋₄alkoxy,     C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkoxy, C₁₋₄alkoxy-C₁₋₄alkoxy,     C₁₋₄alkoxy-carbonyl, C₁₋₄alkoxy-carbonyl-amino,     C₁₋₄alkoxy-carbonyl-amino-C₁₋₄alkoxy, C₂₋₄alkenyl,     C₂₋₄alkenyl-amino-carbonyl, C₃₋₇cycloalkyl,     C₃₋₇cycloalkyl-C₁₋₄alkoxy, C₃₋₇cycloalkenyl, heteroaryl,     heteroaryl-C₁₋₄alkyl, heteroaryl-C₁₋₄alkyl-amino,     heteroaryl-C₁₋₄alkyl-amino-carbonyl,     heteroaryl-C₁₋₄alkyl-carbonyl-amino,     heteroaryl-C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl,     heteroaryl-C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl, heterocyclyl,     heterocyclyl-C₁₋₄alkyl, phenyl, or phenyl-C₁₋₄alkoxy; and -   R_(4a), R_(4b), R_(4c), R_(4d), R_(4e), R_(4f) and R_(4g) are     independently selected from halogen, C₁₋₄alkyl, hydroxyl-C₁₋₄alkyl,     amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino or     hydroxyl-C₁₋₄alkyl-amino; -   wherein a form of the compound is selected from the group consisting     of a prodrug, salt, hydrate, solvate, clathrate, isotopologue,     racemate, enantiomer, diastereomer, stereoisomer, polymorph and     tautomer form thereof.

Another aspect of the present description relates to a compound of Formula (I) selected from a compound of Formula (Ia11), Formula (Ia15), Formula (Ia18) or Formula (Ib1):

-   or a form thereof, wherein (when present), -   X is selected from O, NR₅, or a bond; -   A is selected from phenyl, thiophenyl, indazolyl, pyridinyl,     pyrimidinyl or phenoxy, -   wherein phenyl and phenoxy are each optionally substituted with 1, 2     or 3 substituents each selected from R_(1a), -   wherein thiophenyl, indazolyl, pyridinyl, pyrimidinyl are each     optionally substituted with 1 or 2 substituents each selected from     R_(1a), -   B is selected from 1H-pyrazolyl, piperidinyl,     1,2,3,6-tetrahydropyridinyl, (1R,5S)-8-azabicyclo[3.2.1]octyl,     8-azabicyclo[3.2.1]oct-2-enyl, 2,6-diazaspiro[3.4]octyl or     2,7-diazaspiro[3.5]nonyl, each optionally substituted with 1 or 2     substituents each selected from R_(4a); -   R_(1a) is selected from halogen, hydroxyl, C₁₋₄alkyl,     halo-C₁₋₄alkyl, amino, C₁₋₄alkoxy, or heteroaryl, -   wherein heteroaryl is a monocyclic, bicyclic or polycyclic aromatic     carbon atom ring structure radical in which one or more carbon atom     ring members have been replaced, where allowed by structural     stability, with one or more heteroatoms such as an O, S, or N atom,     optionally substituted with 1 or 2 substituents each selected from     R₃a; -   R_(3a) is selected from nitro or C₁₋₄alkyl; and, -   R_(4a) is C₁₋₄alkyl; -   R_(5a) is hydrogen, C₁₋₄alkyl, or hydroxyl-C₁₋₄alkyl; -   wherein a form of the compound is selected from the group consisting     of a prodrug, salt, hydrate, solvate, clathrate, isotopologue,     racemate, enantiomer, diastereomer, stereoisomer, polymorph and     tautomer form thereof.

Another aspect of the present description relates to a compound of Formula (I) selected from a compound of Formula (Ia11), Formula (Ia15), Formula (Ia18) or Formula (Ib1):

-   or a form thereof, wherein (when present), -   R_(1a) is selected from fluoro, chloro, hydroxyl, methyl,     difluoromethyl, amino, methoxy or 1H-pyrazolyl or 1H-imidazol-1-yl, -   wherein 1H-pyrazolyl is optionally substituted with 1 or 2     substituents each selected from R_(3a); -   R_(3a) is selected from nitro or methyl or amino; and, -   R_(4a) is methyl or ethyl; -   R_(5a) is hydrogen or methyl; -   wherein a form of the compound is selected from the group consisting     of a prodrug, salt, hydrate, solvate, clathrate, isotopologue,     racemate, enantiomer, diastereomer, stereoisomer, polymorph and     tautomer form thereof.

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia1) or a form thereof, wherein substituents R_(1a), R_(1b), and X, when present, are indicated in the table below with multiple substituents separated by a comma; and, “--” indicates that one or more R_(1a), R_(1b), and X substituents are not present:

(Ia1)

Cpd R_(1a) R_(1b) X   1 — — NH   8 2-OH — N(CH₃)  40 1-CH₂CH═CH₂, — N(CH₃) 2-OH 106 1-Br, 7-OH N(CH₃) 2-OH 107 1-Cl, 7-OH N(CH₃) 2-OH

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia2) or a form thereof, wherein substituents R_(1a), R_(1b), and R_(4a), when present, are indicated in the table below with multiple substituents separated by a comma; and, “--” indicates that one or more R_(1a), R_(1b), and R_(4a) substituents are not present:

(Ia2)

Cpd R_(1a) R_(1b) R_(4a)  13 — — — 207 — 7-OH — 208 — 7-OH CH₃ 210 2-CH₃ 7-OH — 222 3-Cl 7-OH — 223 3-Br 7-OH — 224 3-CN 7-OH — 225 3-(1-CH₃-1H-imidazol-4-yl) 7-OH — 226 3-(1H-imidazol-1-yl) 7-OH — 227 3-OH 7-OH — 228 3-CH₂CH₃ 7-OH — 229 3-CH(CH₃)₂ 7-OH — 232 2-CH₃, 7-OH — 4-OCH₃, 233 2-CH₃, 7-OH — 4-(pyrrolidin-1-yl) 234 2-CH₃, 7-OH — 4-(morpholin-4-yl) 235 2-CH₃, 7-OH — 4-N(CH₃)₂ 236 2-CH₃, 7-OH — 4-OCH₂CH₃ 237 2-CH₃, 7-OH — 4-(1-CH₃-1H-pyrazol-4-yl) 240 3-(tetrahydro-2H-pyran-4-yl) 7-OH — 249 4-OCH₃ 7-OH — 250 2-CH₃, 7-OH — 4-(azetidin-1-yl) 251 2-CH₃, 7-OH — 4-CN 252 2-CH₃, 7-OH — 4-cyclopropyl 253 2-CH₃, 7-OH — 4-(3,6-dihydro-2H-pyran-4-yl) 254 2-CH₃, 7-OH — 4-(tetrahydro-2H-pyran-4-yl) 255 2-CH₃, 7-OH — 4-(oxetan-3-yl) 256 4-N(CH₃)₂ 7-OH — 262 2-CN 7-OH — 265 2-C(O)NH₂ 7-OH — 293 3-Cl 7-OH — 294 3-CH(CH₃)₂ 7-OH — 296 2-CH₃, 7-OH — 4-Cl

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia3) or a form thereof, wherein substituents R_(1a), R_(1b) and X, when present, are indicated in the table below with multiple substituents separated by a comma; and, “--” indicates that one or more R_(1a), R_(1b) and X substituents are not present:

Cpd R_(1a) R_(1b) X 11 — — O 15 — — N(CH₃) 218 — 7-OH N(CH₃) 261 1-CN 7-OH N(CH₃) 272 1-CH₃ 7-OH N(CH₃) 275 1-CN, 3-CH₃ 7-OH N(CH₃) 292 3-(OCH₂-phenyl) — N(CH₃)

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia4) or a form thereof, wherein substituents X, R_(1a), R_(1b) and R_(4a), when present, are indicated in the table below; and, “--” indicates that one or more X, R_(1a), R_(1b) and R_(4a) substituents are not present:

Cpd R_(1a) R_(1b) X R_(4a) 10 — — O — 14 — — N(CH₃) — 159 1-(OCH₂-phenyl) — N(CH₃) — 211 — 6-OH N(CH₃) CH₃ 212 — 6-OH N(CH₃) — 213 — 6-OH O — 215 1-cyclopropyl 6-OH N(CH₃) — 216 1-OH 6-OH N(CH₃) — 217 1-CN 6-OH N(CH₃) — 264 1-C(O)NH₂ 6-OH N(CH₃) — 273 1-CH₃ 6-OH N(CH₃) — 274 1,3-(CH₃)₂ 6-OH N(CH₃) — 276 1-NH₂ 6-OH N(CH₃) — 283 1-OCH₂CH₃ 6-OH N(CH₃) — 284 1-OH 6-OH O — 285 3-phenyl 6-OH N(CH₃) — 286 3-CH₃ 6-OH N(CH₃) — 287 3-cyclopropyl 6-OH N(CH₃) — 288 3-CH(CH₃)₂ 6-OH N(CH₃) — 289 3-(CH₂)₂CH₃ 6-OH N(CH₃) — 290 3-CH(CH₃)₂ 6-OH O

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia5) or a form thereof, wherein substituents R_(1a) and R_(1b), when present, are indicated in the table below with multiple substituents separated by a comma; and, “--” indicates that one or more R_(1a) and R_(1b) substituents are not present:

Cpd R_(1a) R_(1b) 12 — — 220 — 6-OH 221 2-CH₃ 6-OH 238 4-OCH₃ 6-OH 241 3-Cl 6-OH 242 3-Br 6-OH 243 3-CH₃ 6-OH 244 3-CH₃ 5-Br, 6-OH 263 2-CN 6-OH 266 2-C(O)NH₂ 6-OH 267 2-CO₂CH₃ 6-OH 297 4-Cl 6-OH 300 — 6-OH

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia6) or a form thereof, wherein substituents R_(1a), when present, are indicated in the table below; and, “--” indicates that one or more R_(1a) substituents are not present:

Cpd R_(1a) 239 — 246 2,3-(CH₃)₂ 247 2-CH₃ 248 3-CH₃

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia7) or a form thereof, wherein substituents R_(1a), when present, are indicated in the table below; and, “--” indicates that one or more R_(1a) substituents are not present:

Cpd R_(1a) 258 — 260 2-CH₃

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia8) or a form thereof, wherein substituents R_(1a) and B, when present, are indicated in the table below; and, “--” indicates that one or more R_(1a) and B substituents are not present:

Cpd R_(1a) B 209 — 6-((3aR,6aS)-5-CH₃-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl) 269 2-CN piperazin-1-yl

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia9) or a form thereof, wherein substituents R_(1a) and B, when present, are indicated in the table below; and, “--” indicates that one or more R_(1a) and B substituents are not present:

Cpd R_(1a) B 214 — 6-((3aR,6aS)-5-CH₃-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl) 270 — piperazin-1-yl 291 3-CH₃ piperazin-1-yl

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia10) or a form thereof, wherein substituents R_(1a) and B, when present, are indicated in the table below; and, “--” indicates that one or more R_(1a) and B substituents are not present:

Cpd R_(1a) B 268 2-CN piperazin-1-yl 271 — 1,2,3,6-tetrahydropyridin-4-yl

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia11) or a form thereof, wherein substituents A, X and R_(4a), when present, are indicated in the table below; and, “--” indicates that one or more A, X and R_(4a) substituents are not present:

Cpd A X R_(4a) 2 benzo[b]thiophen-2-yl N(CH₃) — 4 5-CN-benzo[b]thiophen-2-yl N(CH₃) — 5 quinolin-3-yl NH — 6 benzo[b]thiophen-2-yl O — 9 benzo[b]thiophen-2-yl NH — 16 imidazo[1,2-a]pyridin-6-yl N(CH₃) — 17 6-phenyl-pyridin-3-yl N(CH₃) — 18 6-(1H-pyrrol-1-yl)-pyridin-3-yl N(CH₃) — 19 6-(1H-pyrazol-1-yl)-pyridin-3-yl N(CH₃) — 20 quinoxalin-2-yl N(CH₃) — 21 quinolin-3-yl N(CH₃) — 22 phthalazin-6-yl N(CH₃) — 23 benzo[c][1,2,5]oxadiazol-5-yl NH — 24 benzo[d]thiazol-5-yl NH — 25 2-CH₃-benzo[d]oxazol-6-yl NH — 30 2-(4-CN-phenol) N(CH₃) — 32 2-(4-CF₃-phenol) N(CH₃) — 33 6-(2-F-phenol) N(CH₃) — 34 2-[3,5-(OCH₃)₂-phenol] N(CH₃) — 35 2-[4,5-(OCH₃)₂-phenol] N(CH₃) — 37 2-(4,5-F₂-phenol) N(CH₃) — 41 benzo[b]thiophen-2-yl NH CH₃ 53 2-[4-(1H-pyrazol-1-yl)-phenol] N(CH₃) — 115 2-[3-OH-5-(1H-pyrazol-4-yl)-phenol] N(CH₃) — 116 2-[3-OCH₃-5-(1H-pyrazol-4-yl)-phenol] N(CH₃) — 117 2-[5-(1H-pyrazol-4-yl)-3-OCF₃-phenol] NH — 118 2-[5-(1-CH₃-1H-pyrazol-4-yl)-3-OCF₃-phenol] N(CH₃) — 119 2-[5-(1H-pyrazol-4-yl)-3-OCF₃-phenol] N(CH₃) — 120 2-[5-(1-CH₃-pyridin-2(1H)-one)-3-OCF₃-phenol] N(CH₃) — 121 2-[3-OCH₃-5-(1-CH₃-1H-pyrazol-4-yl)-phenol] N(CH₃) — 122 2-[3-OCH₃-5-(5,6,7,8-tetrahydroimidazo-[1,2- a]pyridin-3-yl)-phenol] N(CH₃) — 123 2-[3-OCH₃-5-(pyridin-3-yl)-phenol] N(CH₃) 124 2-[3-OCH₃-5-(1-cyclopentyl-1H-pyrazol-4- yl)-phenol] N(CH₃) 125 2-[5-(3-OCH₃-phenyl)-3-OCH₃-phenol] N(CH₃) 126 2-[3-benzyloxy-5-(5-CH₃-oxazol-2-yl)-phenol] N(CH₃) 127 2-[3-OCH₂CH₃-5-(5-CH₃-oxazol-2-yl)-phenol] N(CH₃) — 128 2-[3-(OCH₂-cyclopropyl)-5-(5-CH₃-oxazol-2-yl)- phenol] N(CH₃) — 129 5-(2-CH₃-1H-benzo[d]imidazol-6-ol) N(CH₃) — 134 2-[4-(1H-pyrazol-4-yl)-phenol] N(CH₃) — 135 2-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3- yl)-phenol] N(CH₃) — 136 2-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3- yl)-phenol] N(CH₃) — 137 2-[4-(1H-indol-2-yl)-phenol] N(CH₃) — 138 2-[4-(cyclopent-1-en-1-yl)-phenol] N(CH₃) — 139 2-[4-(1H-pyrazol-3-yl)-phenol] N(CH₃) — 140 2-[4-(2-OH-pyridin-4-yl)-phenol] N(CH₃) — 141 2[4-(1-CH₃-pyridin-2(1H)-one)-phenol] O — 142 2-[4-(2-OH-pyridin-4-yl)-phenol] O — 144 2-[4-Cl-5-(1H-pyrazol-4-yl)-phenol] N(CH₃) — 145 2-[4-F-5-(1H-pyrazol-4-yl)-phenol] N(CH₃) — 146 2-[5-F-4-(1H-imidazol-4-yl)-phenol] N(CH₃) — 147 2-[5-F-4-(1H-pyrazol-4-yl)-phenol] N(CH₃) — 148 2-[5-F-(1H-pyrazol-5-yl)-phenol] N(CH₃) — 149 6-OH-1-oxo-2,3-dihydro-1H-inden-5-yl N(CH₃) — 150 6-(1,4-dihydroindeno[1,2-c]-1H-pyrazol-7-ol) N(CH₃) — 151 6-OH-1-OH-imino-2,3-dihydro-1H-inden-5-yl N(CH₃) — 152 6-OH-1-OH-2,3-dihydro-1H-inden-5-yl N(CH₃) — 153 6-(2-NH₂-8H-indeno[1,2-d]thiazol-5-ol) N(CH₃) 154 9-(5,6-dihydroimidazo[5,1-a]isoquinolin-8-ol) N(CH₃) — 155 2-{4-[C(O)NHCH₂-(1-CH₃-1H-pyrazol- 4-yl)]phenol} (CH₃) — 156 2-[4-(4-CH₂OH-1H-pyrazol-1-yl)-phenol] N(CH₃) — 158 3-(OCH₂-phenyl)-isoquinolin-6-yl N(CH₃) — 160 2-[3-F-5-(2-OCH₃-pyridin-4-yl)-phenol] N(CH₃) — 161 4-[1-(4-pyridin-2(1H)-one)-3-F-5-OH-phenyl] N(CH₃) — 162 4-{1-[4-(1-CH₃-pyridin-2(1H)-one)]-3-F-5- OH-phenyl} N(CH₃) — 163 4-{1-[5-(1-CH₃-pyridin-2(1H)-one)]-3-F-5- OH-phenyl} N(CH₃) — 164 2-[3-F-5-(1H-pyrazol-4-yl)-phenol] O — 165 2-(5-Cl-3-F-phenol) N(CH₃) — 166 2-[3-F-5-(1H-pyrazol-4-yl)-phenol] N(CH₃) — 167 2-[3-F-5-(1-CH₃-1H-pyrazol-4-yl)-phenol] N(CH₃) — 219 8-(quinolin-7-ol) N(CH₃) — 230 6-(7-OH-quinolin-2(1H)-one) N(CH₃) — 231 6-(7-OH-1-CH₃-quinolin-2(1H)-one) N(CH₃) — 245 7-(6-OH-1-CH₃-quinolin-4(1H)-one) N(CH₃) — 257 6-(7-OH-quinazolin-4(1H)-one) N(CH₃) — 259 6-(7-OH-1-CH₃-3,4-dihydroquinolin-2(1H)-one) N(CH₃) — 277 7-OH-1,3-(CH₃)2-quinazolin-6-yl-2,4(1H,3H)- dione N(CH₃) — 278 6-OH-benzo[d]oxazol-5-yl-2(3H)-one N(CH₃) — 279 2-CH₃-6-OH-2H-indazol-5-yl N(CH₃) — 280 1-CH₃-6-OH-1H-indazol-5-yl N(CH₃) — 281 7-(6-OH-2-CH₃-isoquinolin-1(2H)-one) N(CH₃) — 282 7-(6-OH-2-CH₂CH₃-isoquinolin-1(2H)-one) O —

Another embodiment of the present description includes a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia11) or a form thereof, wherein substituents A, X and R_(4a), when present, are indicated in the table below; and, “--” indicates that one or more A, X and R_(4a) substituents are not present:

Cpd A X 420 2-OCH₃-4-(4-NO₂-1H-pyrazol-1-yl)phenyl N(CH₃) 428 2,5-F₂-4-(1H-pyrazol-4-yl)phenyl N(CH₃) 430 2,3-F₂-4-(1H-pyrazol-4-yl)phenyl N(CH₃) 431 2,5-F₂-4-(1H-pyrazol-4-yl)phenyl O 434 2-OCH₃-4-(1H-pyrazol-4-yl)phenyl N(CH₃) 435 4-(1H-pyrazol-4-yl)phenyl O 437 2-F-4-(1H-pyrazol-4-yl)phenyl O 438 4-(1-CH₃-1H-pyrazol-4-yl)thiophen-2-yl O 440 2-F-4-OH-phenyl N(CH₃) 442 2-CH₃-2H-indazol-5-yl N(CH₃) 443 2-CH₃-2H-indazol-5-yl O 444 4-Cl-2-OCH₃-phenyl O 445 2-CH₃-pyrazolo[1,5-a]pyridin-3-yl N(CH₃) 446 imidazo[1,2-a]pyridin-6-yl O 447 2-OCH₃-4-(1H-pyrazol-1-yl)phenyl O 448 5-(1H-pyrazol-4-yl)thiophen-2-yl O 449 5-(1-CH₃-1H-pyrazol-4-yl)thiophen-2-yl O 450 4-(1H-pyrazol-4-yl)thiophen-2-yl O 451 2-OH-4-[3,5-(CH₃)₂-1H-pyrazol-4-yl]phenyl O 452 2-F-4-(1H-pyrazol-4-yl)phenyl N(CH₃) 453 2-OCH₃-4-OH-phenyl O 454 2-OCH₃-4-(4-NO₂-1H-pyrazol-1-yl)phenyl O 455 2,4-(OH)₂-phenyl O 456 2-Cl-4-(1H-pyrazol-4-yl)phenyl N(CH₃) 457 5-amino-2-(1H-pyrazol-4-yl)pyrimidin-4-yl O 458 2,6-F₂-4-(1H-pyrazol-4-yl)phenyl O 464 2-(CHF₂)-4-(1H-pyrazol-4-yl)phenyl O 465 2-(CHF₂)-4-(1H-pyrazol-4-yl)phenyl N(CH₃)

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia11) or a form thereof, wherein substituents A, X and R_(4a), when present, are indicated in the table below; and, “--” indicates that one or more A, X and R_(4a) substituents are not present:

Cpd A X 420 2-OCH₃-4-(4-NO₂-1H-pyrazol-1-yl)phenyl N(CH₃) 428 2,5-F₂-4-(1H-pyrazol-4-yl)phenyl N(CH₃) 430 2,3-F₂-4-(1H-pyrazol-4-yl)phenyl N(CH₃) 431 2,5-F₂-4-(1H-pyrazol-4-yl)phenyl O 434 2-OCH₃-4-(1H-pyrazol-4-yl)phenyl N(CH₃) 435 4-(1H-pyrazol-4-yl)phenyl O 437 2-F-4-(1H-pyrazol-4-yl)phenyl O 438 4-(1-CH₃-1H-pyrazol-4-yl)thiophen-2-yl O 440 2-F-4-OH-phenyl N(CH₃) 442 2-CH₃-2H-indazol-5-yl N(CH₃) 443 2-CH₃-2H-indazol-5-yl O 444 4-Cl-2-OCH₃-phenyl O 445 2-CH₃-pyrazolo[1,5-a]pyridin-3-yl N(CH₃) 446 imidazo[1,2-a]pyridin-6-yl O 447 2-OCH₃-4-(1H-pyrazol-1-yl)phenyl O 448 5-(1H-pyrazol-4-yl)thiophen-2-yl O 449 5-(1-CH₃-1H-pyrazol-4-yl)thiophen-2-yl O 450 4-(1H-pyrazol-4-yl)thiophen-2-yl O 451 2-OH-4-[3,5-(CH₃)₂-1H-pyrazol-4- yl]phenyl O 452 2-F-4-(1H-pyrazol-4-yl)phenyl N(CH₃) 453 2-OCH₃-4-OH-phenyl O 454 2-OCH₃-4-(4-NO₂-1H-pyrazol-1-yl)phenyl O 455 2,4-(OH)₂-phenyl O 456 2-Cl-4-(1H-pyrazol-4-yl)phenyl N(CH₃) 457 5-amino-2-(1H-pyrazol-4-yl)pyrimidin-4-yl O 458 2,6-F₂-4-(1H-pyrazol-4-yl)phenyl O 464 2-(CHF₂)-4-(1H-pyrazol-4-yl)phenyl O 465 2-(CHF₂)-4-(1H-pyrazol-4-yl)phenyl N(CH₃)

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia12) or a form thereof, wherein substituents X, R_(1a) and B, when present, are indicated in the table below; and, “--” indicates that one or more X, R_(1a) and B substituents are not present:

Cpd R_(1a) X B 66 H NH azetidin-3-yl 82 OH — piperazin-1-yl 85 H — 1,2,3,6-tetrahydropyridin-4-yl 86 OH — 1,2,3,6-tetrahydropyridin-4-yl 87 OH — 2,2,6,6-tetramethyl-(1,2,3,6- tetrahydropyridin-4-yl) 88 OH — 1-CH₃-(1,2,3,6-tetrahydropyridin-4-yl) 89 OH — piperidin-4-yl 99 H CH₂ piperidin-4-yl

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia13) or a form thereof, wherein substituents X, R_(1a) and R_(4a), when present, are indicated in the table below; and, “--” indicates that one or more X, R_(1a) and R_(4a) substituents are not present:

Cpd X R_(1a) R_(4a) 26 N(CH₃) H — 28 NH H — 31 O H — 90 O OH — 91 N(CH₃) OH — 92 NH OH — 93 N(CH₃) O(CH₂)₃NHCO₂C(CH₃)₃ — 94 N(CH₃) O(CH₂)₃NH₂ — 95 N(CH₃) O(CH₂)₃NHCO₂CH₃ — 96 N(CH₃) O(CH₂)₃OH — 97 N(CH₃) O(CH₂)₃OCH₃ — 98 O O(CH₂)₃-morpholin-4-yl — 103 N(CH₃) CN — 104 N(CH₃) CH₂-1-piperidinyl — 105 N(CH₃) CH₂-pyrrolidin-1-yl — 108 N(CH₃) OCH₃ — 109 N(CH₃) OCH₃ CH₃ 110 N(CH₃) 3,6-dihydro-2H-pyran-4-yl — 111 N(CH₃) tetrahydro-2H-pyran-4-yl — 112 N(CH₃) CHF₂ — 113 N(CH₃) OC(CH₃)₂(CH₂)₂OH — 114 N(CH₃) O(CH₂)₂C(CH₃)₂OH —

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia14) or a form thereof, wherein substituents X and B, when present, are indicated in the table below; and, “--” indicates that one or more X and B substituents are not present:

Cpd X B 55 O piperidin-4-yl 56 O (2S,4R,6R)-2,6-(CH₃)₂-piperidin-4-yl 57 O 2,6-(CH₃)₂-piperidin-4-yl 58 O pyrrolidin-3-yl 59 O 2-CH₃-piperidin-4-yl 60 OCH₂ 1H-pyrrolidin-3-yl 61 O 3-F-piperidin-4-yl 65 — piperazin-1-yl 67 NH azetidin-3-yl 68 — 3,5-(CH₃)₂-piperazin-1-yl 69 — 7-CH₃-2,7-diazaspiro[4.4]non-2-yl 70 — [1,4]diazepan-1-yl 71 — 4-CH₂CH₂OH-piperazin-1-yl 72 — 2,7-diazaspiro[3.5]non-7-yl 73 — 2,7-diazaspiro[3.5]non-7-yl 74 — 3-CH₂OH-piperazin-1-yl 75 — 1,7-diazaspiro[4.4]non-7-yl 76 — 4-NH₂-4-CH₃-piperidin-1-yl 77 — 3-N(CH₃)₂-piperidin-1-yl 79 — 3,3-(CH₃)₂-piperazin-1-yl 80 — 7-CH₂CH₂OH-2,7-diazaspiro[4.4]-nonan-2-yl 83 — 1,2,3,6-tetrahydropyridin-4-yl 84 — piperidin-4-yl 102 O (6S)-6-[(S)-CH(OH)CH₃]-2,2-(CH₃)₂-piperidin-4-yl 133 O 2,2-(CH₃)₂-piperidin-4-yl

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia15) or a form thereof, wherein substituents X, R_(1a) and R_(4a), when present, are indicated in the table below; and, “--” indicates that one or more X, R_(1a) and R_(4a) substituents are not present:

Cpd X R_(1a) R_(4a) 3 NH H — 7 N(CH₃) H — 27 N(CH₃) Cl CH₃ 29 NH Cl CH₃ 36 N(CH₃) OCH₃ — 38 N(CH₃) F — 39 N(CH₃) CN — 42 N(CH₃) C(O)NHCH₂CH═CH₂ — 43 N(CH₃) 1H-pyrazol-1-yl — 44 N(CH₃) 5-CH₃-oxazol-2-yl — 45 N(CH₃) 4-CH₂OH-1H-pyrazole-1-yl — 46 N(CH₃) 1H-imidazole-1-yl — 47 N(CH₃) 4-NH₂-1H-pyrazol-1-yl — 48 N(CH₃) 1H-pyrazol-4-yl — 49 N(CH₃) 3-NH₂-1H-pyrazol-1-yl — 50 N(CH₃) 1-(CH₂CH₂-morpholin-4-yl)-1H-pyrazol-4-yl — 51 N(CH₃) 1-CH₃-1H-pyrazol-4-yl — 52 N(CH₃) 5-NH₂-1H-pyrazol-1-yl — 54 N(CH₂CH₂OH) 1H-pyrazol-1-yl — 62 O 1H-pyrazol-1-yl CH₃ 63 O 1H-pyrazol-1-yl — 64 O 1H-pyrazol-4-yl — 78 NH 1H-pyrazol-1-yl CH₃ 100 CH₂ 1H-pyrazol-1-yl — 130 N(CH₃) Cl — 131 NH 1H-pyrazol-1-yl — 132 NH CN — 143 N(CH₃) 1H-indazol-7-yl — 157 CH₂ 1H-pyrazol-4-yl — 168 N(CH₃) 5-OCH₃-pyridin-3-yl — 169 N(CH₃) 5-pyridin-2-ol — 170 N(CH₃) 4-pyridin-2-ol — 171 N(CH₃) 6-OCH₃-pyridin-3-yl — 172 N(CH₃) 5-(3-CF₃-pyridin-2-ol) — 173 N(CH₃) 5-(1-CH₃-pyridin-2(1H)-one) — 174 N(CH₃) 4-(1-CH₃-pyridin-2(1H)-one) — 175 N(CH₃) 2-OCH₃-pyridin-4-yl — 176 O 4-pyridin-2-ol — 177 N(CH₃) 6-N(CH₃)₂-pyridin-3-yl — 178 O 4-(1-CH₃-pyridin-2(1H)-one) — 179 N(CH₃) pyrimidin-5-yl — 180 N(CH₃) 5-pyridin-3-ol — 181 N(CH₃) 4-(1-cyclopropyl-pyridin-2(1H)-one) — 182 N(CH₃) 1,2,3,6-tetrahydropyridin-4-yl — 183 N(CH₃) cyclopent-1-en-1-yl — 184 N(CH₃) 3,6-dihydro-2H-pyran-4-yl — 185 N(CH₃) imidazo[1,5-a]pyridin-7-yl — 186 N(CH₃) imidazo[1,2-a]pyridin-7-yl — 187 N(CH₃) 2-CH₃-pyridin-4-yl — 188 N(CH₃) 1H-imidazol-2-yl — 189 N(CH₃) 1H-imidazol-4-yl — 190 N(CH₃) imidazo[1,2-a]pyrazin-3-yl — 191 N(CH₃) 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl — 192 N(CH₃) 4-CH₃-1H-imidazol-2-yl — 193 N(CH₃) 1-CH₃-1H-imidazol-4-yl — 194 N(CH₃) 1-CH₃-1H-imidazol-5-yl — 195 N(CH₃) 4-NO₂-1H-imidazol-2-yl — 196 N(CH₃) 2-CH₃-1H-imidazol-4-yl — 197 N(CH₃) 1,2-(CH₃)₂-1H-imidazol-4-yl — 198 N(CH₃) 4-C(O)NH₂-1H-pyrazol-1-yl — 206 N(CH₃) H —

Another embodiment of the present description includes a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia15) or a form thereof, wherein substituents X, R_(1a) and R_(4a), when present, are indicated in the table below; and, “--” indicates that one or more X, R_(1a) and R_(4a) substituents are not present:

(Ia15)

Cpd X R_(1a) R_(4a) 413 NH 1H-pyrazol-4-yl — 414 O 1-CH₃-1H-pyrazol-4-yl — 416 N(CH₃) 5-CH₃-1H-pyrazol-4-yl — 417 O 1H-imidazol-1-yl — 418 O 5-CH₃-1H-pyrazol-4-yl — 419 N(CH₃) 4-NO₂-1H-pyrazol-1-yl — 421 O 4-NH₂-1H-pyrazol-1-yl — 423 O 4-NO₂-1H-pyrazol-1-yl — 460 N(CH₃) 1H-pyrazol-4-yl — 461 O 1H-pyrazol-4-yl —

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia15) or a form thereof, wherein substituents X, R_(1a) and R_(4a), when present, are indicated in the table below; and, “--” indicates that one or more X, R_(1a) and R_(4a) substituents are not present:

(Ia15)

Cpd X R_(1a) 413 NH 1H-pyrazol-4-yl 414 O 1-CH₃-1H-pyrazol-4-yl 416 N(CH₃) 5-CH₃-1H-pyrazol-4-yl 417 O 1H-imidazol-1-yl 418 O 5-CH₃-1H-pyrazol-4-yl 419 N(CH₃) 4-NO₂-1H-pyrazol-1-yl 421 O 4-NH₂-1H-pyrazol-1-yl 423 O 4-NO₂-1H-pyrazol-1-yl 460 N(CH₃) 1H-pyrazol-4-yl 461 O 1H-pyrazol-4-yl

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia16) or a form thereof, wherein substituents R_(1a) and R_(4a), when present, are indicated in the table below; and, “--” indicates that one or more R_(1a) and R_(4a) substituents are not present:

(Ia16)

Cpd R_(1a) R_(4a)  81 1H-pyrazol-1-yl — 199 1H-pyrazol-4-yl (CH₂)₂OH 200 1H-pyrazol-4-yl — 201 1H-pyrazol-4-yl CH₃ 202 4-(1-CH₃-pyridin-2(1H)-one) CH₃ 203 4-(1-CH₃-pyridin-2(1H)-one) CH₃

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia17) or a form thereof, wherein substituent R_(1a), when present, is indicated in the table below; and, indicates that one or more R_(1a) substituents are not present:

(Ia17)

Cpd R_(1a) 204 1H-pyrazol-4-yl 205 4-(1-CH₃-pyridin-2(1H)-one)

Another embodiment of the present description includes a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia18) or a form thereof, wherein substituents X and B, when present, are indicated in the table below; and, “--” indicates that one or more X and B substituents are not present:

(Ia18)

Cpd X B 411 N(CH₃) (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl 412 NH (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl 415 O (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl 422 — 1-CH₃-(1,2,3,6-tetrahydropyridin-4-yl) 424 — 1,2,3,6-tetrahydropyridin-4-yl 425 — 1-CH₃CH₂-(1,2,3,6-tetrahydropyridin-4-yl) 426 N(CH₃) piperidin-4-yl 427 NH piperidin-4-yl 429 — 8-azabicyclo[3.2.1]oct-2-en-3-yl 432 O piperidin-4-yl 433 NH (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl 436 O 2,6-(CH₃)₂-piperidin-4-yl 439 — 2,7-diazaspiro[3.5]non-2-yl 441 O 2,6-(CH₃)₂-piperidin-4-yl 459 — 2,6-diazaspiro[3.4]oct-2-yl

Another embodiment of the method of the present description includes the use of a compound of Formula (Ia) or a form thereof selected from a compound of Formula (Ia18) or a form thereof, wherein substituents X, R_(1a) and B, when present, are indicated in the table below; and, “--” indicates that one or more X, R_(1a) and B substituents are not present:

(Ia18)

Cpd X B 411 N(CH₃) (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl 412 NH (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl 415 O (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl 422 — 1-CH₃-(1,2,3,6-tetrahydropyridin-4-yl) 424 — 1,2,3,6-tetrahydropyridin-4-yl 425 — 1-CH₃CH₂-(1,2,3,6-tetrahydropyridin-4-yl) 426 N(CH₃) piperidin-4-yl 427 NH piperidin-4-yl 429 — 8-azabicyclo[3.2.1]oct-2-en-3-yl 432 O piperidin-4-yl 433 NH (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl 436 O 2,6-(CH₃)₂-piperidin-4-yl 439 — 2,7-diazaspiro[3.5]non-2-yl 441 O 2,6-(CH₃)₂-piperidin-4-yl 459 — 2,6-diazaspiro[3.4]oct-2-yl

Another embodiment of the method of the present description includes the use of a compound of Formula (Ib) or a form thereof selected from a compound of Formula (Ib1) or a form thereof, wherein substituent A is indicated in the table below:

(Ib1)

Cpd A 302 6-(naphthalen-2-ol) 320 6-(naphthalen-2,7-diol) 331 7-OCH₃-quinolin-6-yl 332 7-OH-quinolin-6-yl 337 2-CN-7-OCH₃-quinolin-6-yl 355 3-F-5-(1H-pyrazol-4-yl)-pyridin-2-yl 364 2-(6-OCH₃-3,4-dihydroisoquinolin-1(2H)-one) 392 6-OH-1-oxo-2,3-dihydro-1H-inden-5-yl 401 3-(4-OCH₃-1-CH₃-quinolin-2(1H)-one) 402 3-(4-OH-1-CH₃-quinolin-2(1H)-one) 403 3-(quinolin-2(1H)-one) 404 3-(1-OCH₃-quinolin-2(1H)-one) 408 5-CN-benzo[b]thiophen-2-yl 409 3-Cl-benzo[b]thiophen-2-yl

Another embodiment of the present description includes a compound of Formula (Ib) or a form thereof selected from a compound of Formula (Ib1) or a form thereof, wherein substituent A is indicated in the table below:

Cpd A 462 3-(1H-pyrazol-4-yl)phenoxy 463 4-(1H-pyrazol-4-yl)phenoxy

Another embodiment of the method of the present description includes the use of a compound of Formula (Ib) or a form thereof selected from a compound of Formula (Ib1) or a form thereof, wherein substituent A is indicated in the table below:

(Ib1)

Cpd A 462 3-(1H-pyrazol-4-yl)phenoxy 463 4-(1H-pyrazol-4-yl)phenoxy

Another embodiment of the method of the present description includes the use of a compound of Formula (Ib) or a form thereof selected from a compound of Formula (Ib2) or a form thereof, wherein substituent A is indicated in the table below:

(Ib2)

Cpd A 321 6-naphthalen-2,7-diol

Another embodiment of the method of the present description includes the use of a compound of Formula (Ib) or a form thereof selected from a compound of Formula (Ib3) or a form thereof, wherein substituents R_(1a), R_(1b) and B, when present, are indicated in the table below; and, “--” indicates that one or more R_(1a), R_(1b) and B substituents are not present:

(Ib3)

Cpd R_(1a) R_(1b) B 329 1H-pyrazol-1-yl OCH₃ 1,2,3,6-tetrahydropyridin-4-yl 330 1H-pyrazol- 1-yl OH piperazin-l-yl 381 1H-pyrazol-1-yl Cl 5-((3aR,6aR)-1-CH₃- hexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl) 382 1H-pyrazol-1-yl Cl 2-NHCH(CH₃)2-morpholin-4-yl 383 1H-pyrazol-1-yl Cl 2-OCH₃-2,7- diazaspiro[4.5]decan-7-yl 385 1-CH₃-1H- OCH₃ 5-((3aR,6aS)-5-CH₃- pyrazol-4-yl hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl) 394 1-CH₃-1H- OH 5-((3aR,6aS)-5-CH₃- pyrazol-4-yl hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl) 406 1H-pyrazol-1-yl Cl 2,7-diazaspiro [4.5] decan-2-yl 407 1H-pyrazol-1-yl Cl (3R)-(3-(R)-CH₂OH)- piperazin-1-yl

Another embodiment of the ccpresent description includes the use of a compound of Formula (Ib) or a form thereof selected from a compound of Formula (Ib4) or a form thereof, wherein substituents R_(1a), R_(1b), R_(1c), R_(1d) (each representative of the scope of R₁) and X, when present, are indicated in the table below; and, “--” indicates that one or more R_(1a), R_(1b), R_(1c), R_(1d) and X substituents are not present:

(Ib4)

Cpd R_(1a) R_(1b) R_(1c) R_(1d) X 301 1H-pyrazol-1-yl OCH₃ H H N(CH₃) 305 1H-pyrazol-1-yl OCH₃ H H N(CH₃) 306 1-CH₃-1H-pyrazol-4-yl OCH₃ H H N(CH₃) 307 1H-pyrazol-4-yl OCH₃ H H N(CH₃) 308 4-(1-CH₃-pyridin-2(1H)-one) OCH₃ H H N(CH₃) 309 5-pyridin-2-ol OCH₃ H H N(CH₃) 310 5-(1-CH₃-pyridin-2(1H)-one) OCH₃ H H N(CH₃) 311 1-CH₃-1H-pyrazol-4-yl CH₃ H H N(CH₃) 312 4-(1-CH₃-pyridin-2(1H)-one) OCH₃ H H N(CH₃) 313 3,5-(CH₃)₂-1H-pyrazol-4-yl OCH₃ H H N(CH₃) 314 1-CH₃-1H-pyrazol-4-yl CF₃ H H N(CH₃) 315 1-CH₃-1H-pyrazol-4-yl OH H H N(CH₃) 316 1H-pyrazol-1-yl OH H H N(CH₃) 317 5-(1-CH₃-pyridin-2(1H)-one) OH H H N(CH₃) 318 4-(1-CH₃-pyridin-2(1H)-one) OH H H N(CH₃) 319 5-pyridin-2-ol OH H H N(CH₃) 324 H OH 1H-pyrazol- H N(CH₃) 1-yl 325 1-CH₃-1H-pyrazol-4-yl H H Cl N(CH₃) 326 1-CH₃-1H-pyrazol-4-yl OH H Cl N(CH₃) 327 1-CH₃-1H-pyrazol-4-yl H H Cl N(CH₃) 328 5-CH₃-oxazol-2-yl OH H OCH₃ N(CH₃) 333 CN OCH₃ H H N(CH₃) 334 CN F H H N(CH₃) 335 CO₂CH₃ F H H N(CH₃) 336 3-NHCH₃-1H-pyrazol-1-yl OCH₃ H H N(CH₃) 338 4-(1-CH₃-pyridin-2(1H)-one) OCH₃ H H N(CH₃) 339 4-(1-CH₃-pyridin-2(1H)-one) Cl H H N(CH₃) 340 1H-pyrazol-4-yl Cl H H N(CH₃) 341 4,5,6,7- Cl H H N(CH₃) tetrahydropyrazolo[1,5-a] pyridin-3-yl 343 1-CH₃-1H-pyrazol-4-yl Cl H H O 344 6-OCH₃-pyridin-3-yl Cl H H N(CH₃) 345 6-NH₂-pyridin-3-yl F H H N(CH₃) 346 3-CH₃-1H-pyrazol-5-yl F H H N(CH₃) 347 1H-pyrazol-5-yl F H H N(CH₃) 348 1H-pyrazol-4-yl H F F N(CH₃) 349 1H-pyrazol-5-yl H F F N(CH₃) 350 1H-pyrazol-4-yl F F H N(CH₃) 351 1H-pyrazol-5-yl F F H N(CH₃) 352 1H-pyrazol-4-yl F H F N(CH₃) 354 1H-pyrazol-4-yl Cl F H N(CH₃) 356 2-NH₂-pyrimidin-4-yl Cl H H N(CH₃) 357 H Cl 2-NH₂- H N(CH₃) pyrimidin-4-yl 358 2,4-(CH₃)2-thiazol-5-yl F F H N(CH₃) 359 2,4-(CH₃)2-thiazol-5-yl H F F N(CH₃) 360 4-(1-CH₃-pyridin-2(1H)-one) OH H OCF₃ N(CH₃) 361 1H-pyrazol-4-yl OCH₃ H F N(CH₃) 363 1H-pyrazol-4-yl OCH₃ F F N(CH₃) 365 1H-pyrazol-1-yl Cl H H N(CH₃) 366 1H-1,2,3-triazol-1-yl Cl H H N(CH₃) 367 2H-1,2,3-triazol-2-yl Cl H H N(CH₃) 368 1H-1,2,4-triazol-1-yl Cl H H N(CH₃) 369 3-NH₂-1H-pyrazol-1-yl Cl H H N(CH₃) 371 1H-imidazol-1-yl Cl H H N(CH₃) 372 1H-imidazol-1-yl F H H N(CH₃) 373 1H-pyrazol-5-yl OCH₃ H H N(CH₃) 374 2,4-(CH₃)2-thiazol-5-yl OCH₃ H H N(CH₃) 375 pyridin-3-yl OCH₃ H H N(CH₃) 376 1H-pyrazol-4-yl F H H N(CH₃) 377 2-OCH₃-pyridin-4-yl OCH₃ H H N(CH₃) 378 6-OCH₃-pyridin-3-yl OCH₃ H H N(CH₃) 387 1H-pyrazol-1-yl OH H H N(CH₃) 388 5-(pyridin-2(1H)-one) Cl H H N(CH₃) 389 3-NHCH₃-1H-pyrazol-1-yl OH H H N(CH₃) 390 1H-pyrazol-4-yl OH H F N(CH₃) 391 1H-pyrazol-4-yl OH F F N(CH₃) 393 1H-pyrazol-4-yl OH H H N(CH₃) 397 1H-pyrazol-4-yl OH H Cl N(CH₃) 398 1H-pyrazol-1-yl OCH₃ H H CH₂ 410 1H-pyrazol-4-yl OCH₃ H H N(CH₃)

Another embodiment of the method of the present description includes the use of a compound of Formula (Ib) or a form thereof selected from a compound of Formula (Ib5) or a form thereof, wherein substituents R_(1a), R_(1b), R_(1c), R_(1d) (each representative of the scope of R₁) and R_(4a), when present, are indicated in the table below; and, “--” indicates that one or more R_(1a), R_(1b), R_(1c), R_(1d) and R_(4a) substituents are not present:

(Ib5)

Cpd R_(1a) R_(1b) R_(1c) R_(1d) R_(4a) 353 1H-pyrazol-4-yl F F H — 362 1H-pyrazol-4-yl OCH₃ H F CH₃ 370 1H-imidazol-1-yl Cl H H CH₃ 379 1-CH₃-1H-pyrazol-4-yl Cl H H CH₃ 380 1H-pyrazol-4-yl Cl H H CH₃ 384 1H-pyrazol-4-yl F H H CH₃ 396 1H-pyrazol-4-yl F H OH — 405 1H-pyrazol-4-yl Cl H H —

Another embodiment of the method of the present description includes the use of a compound of Formula (Ib) or a form thereof selected from a compound of Formula (Ib6) or a form thereof, wherein substituents R_(1a), R_(1b), R_(1c) and R_(1d) (each representative of the scope of R₁), when present, are indicated in the table below; and, “--” indicates that one or more R_(1a), R_(1b), R_(1c) and Rid substituents are not present:

(1b6)

Cpd R_(1a) R_(1b) R_(1c) R_(1d) 386 1-CH₃-1H-pyrazol-4-yl OCH₃ H H 395 1-CH₃-1H-pyrazol-4-yl OH H H 399 1H-pyrazol-4-yl H F F 400 1H-pyrazol-4-yl OH H F

Another embodiment of the method of the present description includes the use of a compound of Formula (Ib) or a form thereof selected from a compound of Formula (Ib7) or a form thereof, wherein substituent Rib, when present, is indicated in the table below:

(1b7)

Cpd R_(1b) 304 OCH₃ 322 OH

Another embodiment of the method of the present description includes the use of a compound of Formula (Ib) or a form thereof selected from a compound of Formula (Ib8) or a form thereof, wherein substituent R_(1b), when present, is indicated in the table below:

(Ib8)

Cpd R_(1b) 303 OCH₃ 323 OH

An embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof to the subject, selected from the group consisting of:

wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

In another aspect, the compound of Formula (I) or a form thereof includes a compound selected from the group consisting of:

wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

Another embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof (wherein compound number (#¹) indicates that the salt form was isolated) to the subject, selected from the group consisting of:

Cpd Name  1 6-(naphthalen-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine  2 6-(benzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3- amine  3 2-(6-(2,2,6,6-tetramethylpiperidin-4-yl-amino)-pyridazin-3-yl)phenol  4 2-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzo[b]- thiophene-5-carbonitrile  5 6-(quinolin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine  6 3-(benzo[b]-thiophen-2-yl)-6-(2,2,6,6-tetramethylpiperidin-4-yl-oxy)pyridazine  7 2-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)-pyridazin-3-yl)phenol  8 6-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)-pyridazin-3-yl)naphthalen-2-ol  9 6-(benzo[b]-thiophen-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine  10 7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline  11 6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline  12 N-methyl-6-(quinolin-7-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine  13 N-methyl-6-(quinolin-6-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine  14 6-(isoquinolin-7-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine  15 6-(isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine  16 6-(imidazo[1,2-a]pyridin-6-yl-pyridazin-3-yl)-methyl-(2,2,6,6-tetramethylpiperidin-4- yl)-amine  17 N-methyl-6-(6-phenylpyridin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3- amine  18 6-(6-(1H-pyrrol-1-yl)pyridin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine  19 6-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine  20 methyl-(6-quinoxalin-2-yl-pyridazin-3-yl)-(2,2,6,6-tetramethylpiperidin-4-yl)-amine  21 methyl-(6-quinolin-3-yl-pyridazin-3-yl)-(2,2,6,6-tetramethylpiperidin-4-yl)-amine  22 N-methyl-6-(phthalazin-6-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine  23 6-(benzo[c][1,2,5]oxa-diazol-5-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3- amine  24 6-(benzo[d]thiazol-5-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine  25 6-(2-methylbenzo-[d]oxazol-6-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3- amine  26 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol  27 5-chloro-2-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol  28 3-(6-(2,2,6,6-tetramethylpiperidin-4-yl-amino)pyridazin-3-yl)naphthalen-2-ol  29 5-chloro-2-(6-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyridazin-3-yl)phenol  30 4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)benzonitrile  31 3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalen-2-ol   32¹ 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4- (trifluoromethyl)phenol  33 2-fluoro-6-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)-amino)-pyridazin-3-yl)phenol  34 3,5-dimethoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol  35 4,5-dimethoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol  36 5-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol  37 4,5-difluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol  38 5-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol  39 3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)benzonitrile  40 1-allyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalen-2-ol  41 6-(benzo[b]thiophen-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine  42 N-allyl-3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)benzamide  43 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1- yl)phenol  44 5-(5-methyl-oxazol-2-yl)-2-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)-amino)- pyridazin-3-yl)phenol  45 5-(4-hydroxymethyl)-1H-pyrazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol  46 5-(1H-imidazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)phenol  47 5-(4-amino-1H-pyrazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol  48 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4- yl)phenol  49 5-(3-amino-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol  50 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-(2- morpholino-ethyl)-1H-pyrazol-4-yl)phenol  51 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H- pyrazol-4-yl)phenol  52 5-(5-amino-1H-pyrazol-1-yl)-2-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol   53¹ 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-1- yl)phenol  54 2-((6-((2-hydroxy-ethyl)-(2,2,6,6-tetramethylpiperidin-4-yl)-amino)-pyridazin-3-yl)-5- pyrazol-1-yl)phenol  55 2-(6-(piperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  56 2-(6-(((2S,4R,6R)-2,6-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1- yl)phenol  57 2-(6-((-2,6-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  58 5-(1H-pyrazol-1-yl)-2-(6-(pyrrolidin-3-yl-oxy)pyridazin-3-yl)phenol  59 2-(6-(((2S,4S)-2-methylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  60 (5-(1H-pyrazol-1-yl)-2-(6-(pyrrolidin-3-ylmethoxy)pyridazin-3-yl)phenol  61 2-(6-((3-fluoropiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  62 2-(6-(1,2,2,6,6-pentamethyl-piperidin-4-yl-oxy)-pyridazin-3-yl)-5-(1H-pyrazol-1- yl)phenol  63 5-1H-pyrazol-1-yl-2-(6-(2,2,6,6-tetramethylpiperidin-4-yl-oxy)-pyridazin-3-yl)phenol  64 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol   65¹ 2-(6-piperazin-1-yl-pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  66 3-(6-(azetidin-3-ylamino)-pyridazin-3-yl)naphthalen-2-ol  67 2-(6-(azetidin-3-ylamino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  68 2-(6-(3,5-dimethylpiperazin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  69 2-(6-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridazin-3-yl)-5-(1H-pyrazol-1- yl)phenol  70 2-(6-(1,4-diazepan-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  71 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  72 2-[6-(3,6-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  73 2-[6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  74 2-(6-(3-(hydroxymethyl)piperazin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  75 2-(6-(1,7-diazaspiro[4.4]nonan-7-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  76 2-(6-(4-amino-4-methylpiperidin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  77 2-(6-(3-(dimethylamino)piperidin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  78 2-(6-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)-pyridazin-3-yl)-5-1H-pyrazol-1-yl- phenol  79 2-(6-(3,3-dimethylpiperazin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol  80 2-(6-(7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]-nonan-2-yl)pyridazin-3-yl)-5-(1H-pyrazol- 1-yl)phenol  81 2-[6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H- pyrazol-1-yl)phenol   82¹ 3-(6-(piperazin-1-yl)pyridazin-3-yl)naphthalene-2,7-diol  83 5-(1H-pyrazol-1-yl)-2-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)phenol  84 2-(6-piperidin-4-yl-pyridazin-3-yl)-5-1H-pyrazol-1-yl-phenol  85 3-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalen-2-ol   86¹ 3-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol  87 3-(6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7- diol   88¹ 3-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol   89¹ 3-(6-(piperidin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol  90 3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalene-2,7-diol  91 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7- diol  92 3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol  93 tert-butyl (3-((7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)naphthalen-2-yl)oxy)propyl)carbamate  94 7-(3-amino-propoxy)-3-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)-amino)- pyridazin-3-yl)naphthalen-2-ol  95 N-(3-((7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalen-2-yl)oxy)propyl)acetamide  96 7-(3-hydroxypropoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)naphthalen-2-ol  97 7-(3-methoxypropoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)naphthalen-2-ol  98 7-(2-morpholinoethoxy)-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3- yl)naphthalen-2-ol  99 3-(6-(piperidin-4-ylmethyl)pyridazin-3-yl)naphthalen-2-ol 100 5-(1H-pyrazol-1-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3- yl)phenol 101 3-methoxy-2-(6-(methyl(2,2,6-trimethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5- methyloxazol-2-yl)phenol 102 2-(6-((6S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-yloxy)pyridazin-3-yl)-5- (1H-pyrazol-1-yl)phenol 103 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2- naphthonitrile 104 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7- (piperidinylmethyl)naphthalen-2-ol 105 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7- (pyrrolidinylmethyl)naphthalen-2-ol 106 1-bromo-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalene-2,7-diol 107 1-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalene-2,7-diol 108 7-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalene-2-ol 109 7-methoxy-3-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalen-2-ol 110 7-(3,6-dihydro-2H-pyran-4-yl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)naphthalen-2-ol 111 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(tetrahydro-2H- pyran-4-yl)naphthalene-2-ol 112 7-(difluoromethyl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalen-2-ol 113 7-((4-hydroxy-2-methylbutan-2-yl)oxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)naphthalen-2-ol 114 7-(3-hydroxy-3-methylbutoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)naphthalen-2-ol 115 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4- yl)benzene-1,3-diol 116 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5- (1H-pyrazol-4-yl)phenol 117 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3- (trifluoromethoxy)phenol 118 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H- pyrazol-4-yl)-3-(trifluoromethoxy)phenol 119 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4- yl)-3-(trifluoromethoxy)phenol 120 4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5- (trifluoromethoxy)phenyl)-1-methylpyridin-2(1H)-one 121 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1- methyl-1H-pyrazol-4-yl)phenol 122 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5- (5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)phenol 123 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5- (pyridine-3-yl)phenol 124 5-(1-cyclopentyl-1H-pyrazol-4-yl)-3-methoxy-2-(6-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol 125 3',5-dimethoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)- (1,1′-biphenyl)-3-ol 126 3-(benzyloxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5- (5-methyloxazol-2-yl)phenol 127 3-ethoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5- methyloxazol-2-yl)phenol 128 3-(cyclopropylmethoxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)- pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol 129 2-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1H- benzo[d]imidazol-6-ol 130 5-chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol 131 5-(1H-pyrazol-1-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol 132 3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile 133 2-(6-((2,2-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 134 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-4- yl)phenol 135 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridin-3-yl)-4-(4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenol 136 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenol 137 4-(1H-indol-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol 138 4-(cyclopent-1-en-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 139 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-3- yl)phenol 140 4-(4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)pyridin-2-ol 141 4-(4-hydroxy-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl)-1- methylpyridin-2(1H)-one 142 4-(4-hydroxy-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3- yl)phenyl)pyridin-2-ol 143 5-(1H-indazol-7-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol 144 4-chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 145 4-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 146 5-fluoro-4-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 147 5-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H- pyrazol-4-yl)phenol 148 5-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H- pyrazol-5-yl)phenol 149 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3- dihydro-1H-inden-1-one 150 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1,4- dihydroindeno[1,2-c]-1H-pyrazol-7-ol  151¹ 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3- dihydro-1H-inden-1-one oxime 152 5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H- indene-1,6-diol  153¹ 2-amino-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-8H- indeno[1,2-d]thiazol-5-ol  154¹ 9-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-8-ol 155 4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-((1- methyl-1H-pyrazol-4-yl)methyl)benzamide 156 4-(4-(hydroxymethyl)-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 157 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3- yl)phenol 158 6-(3-(benzyloxy)isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 159 6-(1-(benzyloxy)isoquinolin-7-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine  160¹ 3-fluoro-5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol  161¹ 4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)phenyl)pyridin-2(1H)-one  162¹ 4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)phenyl)-1-methylpyridin-2(1H)-one  163¹ 5-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)phenyl)-1-methylpyridin-2(1H)-one  164¹ 3-fluoro-5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3- yl)phenol  165¹ 5-chloro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol  166¹ 3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol  167¹ 3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1- methyl-1H-pyrazol-4-yl)phenol 168 5-(5-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 169 5-(3-hydroxy-4-(6-methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)pyridin-2-ol 170 4-(3-hydroxy-4-(6-methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)pyridin-2-ol 171 5-(6-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 172 5-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)-3-(trifluoromethyl)pyridin-2-ol 173 5-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)-1-methylpyridin-2(1H)-one 174 4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)-1-methylpyridin-2(1H)-one 175 5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 176 4-(3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3- yl)phenyl)pyridin-2-ol 177 5-(6-(dimethylamino)pyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 178 4-(3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl)-1- methylpyridin-2(1H)-one 179 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(pyrimidin-5- yl)phenol 180 5-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)pyridin-3-ol 181 1-cyclopropyl-4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenyl)pyridin-2(1H)-one 182 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1,2,3,6- tetrahydropyridin-4-yl)phenol 183 5-(cyclopent-1-en-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 184 5-(3,6-dihydro-2H-pyran-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 185 5-(imidazo[1,5-a]pyridin-7-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 186 5-(imidazo[1,2-a]pyridin-7-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 187 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(2- methylpyridin-4-yl)phenol 188 5-(1H-imidazol-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)phenol 189 5-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)phenol 190 5-(imidazo[1,2-a]pyrazin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 191 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5,6,7,8- tetrahydroimidazo[1,2-a]pyrazin-3-yl)phenol 192 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(4-methyl-1H- imidazol-2-yl)phenol 193 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H- imidazol-4-yl)phenol 194 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H- imidazol-5-yl)phenol 195 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(4-nitro-1H- imidazol-2-yl)phenol 196 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(2-methyl-1H- imidazol-4-yl)phenol 197 5-(1,2-dimethyl-1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 198 1-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)-1H-pyrazole-4-carboxamide 199 2-(6-((3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin- 3-yl)-5-(1H-pyrazol-4-yl)phenol 200 2-[6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 201 2-(6-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5- (1H-pyrazol-4-yl)phenol 202 4-(3-hydroxy-4-(6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3- yl)phenyl)-1-methylpyridin-2(1H)-one 203 4-(3-hydroxy-4-(6-((3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)- yl)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one 204 2-(6-(2,7-diazaspiro[4.5]decan-2-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol 205 4-(4-(6-(2,7-diazaspiro[4.5]decan-2-yl)pyridazin-3-yl)-3-hydroxyphenyl)-1- methylpyridin-2(1H)-one 206 2-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)-amino)-pyridazin-3-yl)phenol 207 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol 208 6-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol 209 6-(6-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3- yl)quinolin-7-ol 210 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 7-ol 211 7-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol 212 7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol 213 7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline-6-ol 214 7-(6-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3- yl)isoquinolin-6-ol 215 1-cyclopropyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 216 7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinoline-1,6- diol 217 6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinoline-1-carbonitrile 218 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-7-ol 219 8-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol 220 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-6-ol 221 2-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 6-ol 222 3-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 7-ol 223 3-bromo-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 7-ol 224 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoline-3-carbonitrile 225 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(1-methyl-1H- imidazol-4-yl)quinolin-7-ol  226¹ 3-(1H-imidazol-1-yl)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)quinolin-7-ol 227 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoline-3,7-diol 228 3-ethyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 7-ol 229 3-isopropyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol 230 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-2(1H)-one  231¹ 7-hydroxy-1-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-2(1H)-one 232 4-methoxy-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol 233 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4- (pyrrolidin-1-yl)quinolin-7-ol 234 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4- morpholinoquinolin-7-ol 235 4-(dimethylamino)-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)quinolin-7-ol 236 4-ethoxy-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol 237 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1- methyl-1H-pyrazol-4-yl)quinolin-7-ol  238¹ 4-methoxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-6-ol  239¹ 7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoxalin-6-ol 240 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(tetrahydro-2H- pyran-4-yl)quinolin-7-ol 241 3-chloro-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 6-ol 242 3-bromo-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 6-ol 243 3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 6-ol 244 5-bromo-3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-6-ol 245 6-hydroxy-1-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-4(1H)-one 246 2,3-dimethyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-6-ol 247 2-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoxalin-6-ol 248 3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoxalin-6-ol 249 4-methoxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol 250 4-(azetidin-1-yl)-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)quinolin-7-ol 251 7-hydroxy-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolone-4-carbonitrile 252 4-cyclopropyl-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)-quinolin-7-ol 253 4-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)quinolin-7-ol  254¹ 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4- (tetrahydro-2H-pyran-4-yl)quinolin-7-ol 255 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4- (oxetan-3-yl)quinolin-7-ol 256¹ 4-(dimethylamino)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)-quinolin-7-ol 257 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinazolin-4(1H)-one 258 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinazolin-7-ol 259 7-hydroxy-1-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)-3,4-dihydroquinolin-2(1H)-one 260 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinazolin-7-ol 261 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinoline-1-carbonitrile 262 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoline-2-carbonitrile 263 6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-2-carbonitrile 264 6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinoline-1-carboxamide 265 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-2-carboxamide 266 6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoline-2-carboxamide 267 methyl 6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoline-2-carboxylate 268 6-hydroxy-7-(6-(piperazin-1-yl)pyridazin-3-yl)quinoline-2-carbonitrile 269 7-hydroxy-6-(6-(piperazin-1-yl)pyridazin-3-yl)quinoline-2-carbonitrile 270 7-(6-(piperazin-1-yl)pyridazin-3-yl)isoquinolin-6-ol 271 7-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)quinolin-6-ol 272 1-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-7-ol 273 1-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 274 1,3-dimethyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 275 7-hydroxy-3-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinoline-1-carbonitrile 276 1-amino-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 277 7-hydroxy-1,3-dimethyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)quinazoline-2,4(1H,3H)-dione 278 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)benzo[d]oxazol-2(3H)-one 279 2-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2H- indazol-6-ol 280 1-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1H- indazol-6-ol  281¹ 6-hydroxy-2-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-1(2H)-one 282 2-ethyl-6-hydroxy-7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3- yl)isoquinolin-1(2H)-one 283 1-ethoxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 284 7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline-1,6-diol 285 7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-pyridazin-3-yl)-3- phenylisoquinolin-6-ol 286 3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 287 3-cyclopropyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 288 3-isopropyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 289 3-propyl-7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)-pyridazin-3-yl)isoquinolin-6-ol 290 3-isopropyl-7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)-pyridazin-3-yl)isoquinolin-6- ol 291 3-methyl-7-(6-(piperazin-1-yl)pyridazin-3-yl)isoquinolin-6-ol 292 6-(3-(benzyloxy)isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 293 3-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 7-ol 294 3-isopropyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol 295 3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoxalin-6-ol 296 4-chloro-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol 297 4-chloro-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 6-ol 300 7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-6-ol 301 5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 302 6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalen- 2-ol 303 5-(2-methoxyquinolin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4- thiadiazol-2-amine 304 5-(3-methoxy-naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4- thiadiazol-2-amine 305 5-(2-methoxy-4-(1H-pyrazol-1yl)phenyl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 306 5-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 307 5-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 308 4-(3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin-2(1H)-one 309 5-(3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)pyridin-2-ol 310 5-(3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin-2(1H)-one 311 N-methyl-5-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 312 1-methyl-4-(4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-3-(trifluoromethoxy)phenyl)pyridin-2(1H)-one 313 5-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 314 5-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 315 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4,-thiadiozol-2-yl-5-(1- methyl-1H-pyrazol-4-yl)phenol 316 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4,-thiadiozol-2-yl-5-(1H- pyrazol-1-yl)phenol 317 5-(3-hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin-2(1H)-one 318 4-(3-hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin-2(1H)-one 319 5-(3-hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)pyridin-2-ol 320 3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)naphthalene-2,7-diol 321 3-(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazol-2- yl)naphthalene-2,7-diol  322¹ 3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalen- 2-ol 323 3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2- ol 324 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-4-(1H- pyrazol-1-yl)phenol 325 5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 326 3-chloro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)- 5-(1-methyl-1H-pyrazol-4-yl)phenol 327 5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 328 3-methoxy-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-methyloxazol-2-yl)phenol 329 2-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,3,4- thiadiazole 330 2-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-1-yl)phenol 331 5-(7-methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4- thiadiazole-2-amine 332 6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-7- ol 333 3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)benzonitrile 334 3-fluoro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)benzonitrile 335 methyl-3-fluoro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol- 2-yl)benzoate 336 5-(2-methoxy-4-(3-(methylamino)-1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 337 7-methoxy-6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)quinoline-2-carbonitrile 338 4-(3-methoxy-4-(5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin-2(1H)-one 339 4-(3-chloro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin-2(1H)-one 340 5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 341 5-(2-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine  342¹ N-methyl-5-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 343 2-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-((2,2,6,6-tetramethylpiperidin-4- yl)oxy-1,3,4-thiadiazole 344 5-(2-chloro-4-(6-methoxypyridin-3-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 345 5-(4-(6-aminopyridin-3-yl)-2-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 346 5-(2-fluoro-4-(3-methyl-1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 347 5-(2-fluoro-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 348 5-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 349 5-(2,3-difluoro-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 350 5-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 351 5-(2,5-difluoro-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 352 5-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 353 2-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 354 5-(2-chloro-5-fluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 355 5-(3-fluoro-5-(1H-pyrazol-4-yl)pyridin-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 356 5-(4-(2-aminopyrimidin-4-yl)-2-chlorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 357 5-(5-(2-aminopyrimidin-4-yl)-2-chlorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 358 5-(4-(2,4-dimethylthiazol-5-yl)-2,5-difluorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 359 5-(4-(2,4-dimethylthiazol-5-yl)-2,3-difluorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 360 4-(3-hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(trifluoromethoxy)phenyl)-1-methylpyridin-2(1H)-one 361 5-(2-fluoro-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 362 2-(2-fluoro-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 363 5-(2,3-difluoro-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 364 6-methoxy-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-3,4-dihydroisoquinolin-1-(2H)-one 365 5-(2-chloro-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 366 5-(2-chloro-4-(1H-1,2,3-triazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 367 5-(2-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 368 5-(2-chloro-4-(1H-1,2,4-triazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 369 5-(4-(3-amino-1H-pyrazol-1-yl)-2-chlorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 370 2-(2-chloro-4-(1H-imidazol-1-yl)phenyl)-5-((3aR,6aS)-5- methylhexahydropyrrolo[3,4c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 371 5-(2-chloro-4-(1H-imidazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 372 5-(2-fluoro-4-(1H-imidazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 373 5-(2-methoxy-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 374 5-(4-(2,4-dimethylthiazol-5-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 375 5-(2-methoxy-4-(pyridin-3-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 376 5-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 377 5-(2-methoxy-4-(2-methoxypyridin-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 378 5-(2-methoxy-4-(6-methoxypyridin-3-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 379 2-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 380 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 381 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aR)-1-methylhexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)-1,3,4-thiadiazole 382 1-(4-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)morpholin-2-yl)- N,N-dimethylmethanamine 383 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-(2-methyl-2,7-diazaspiro[4.5]decan-7-yl)- 1,3,4-thiadiazole 384 2-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 385 2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2,6-diazaspiro[3.5]nonan-2-yl)- 1,3,4-thiadiazole 386 2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)- 1,3,4-thiadiazole 387 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H- pyrazol-1-yl)phenol 388 5-(3-chloro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)pyridin-2(1H)-one 389 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(3- (methylamino)-1H-pyrazol-1-yl)phenol 390 3-fluoro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5- (1H-pyrazol-4-yl)phenol 391 3,4-difluoro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-4-yl)phenol 392 6-hydroxy-5-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-2,3-dihydro-1H-inden-1-one 393 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H- pyrazol-4-yl)phenol 394 2-(5-(2,6-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4- yl)phenol 395 2-(5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4- yl)phenol  396¹ 3-fluoro-2-(5-((aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-4-yl)phenol 397 3-chloro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)- 5-(1H-pyrazol-4-yl)phenol 398 2-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-((2,2,6,6-tetramethylpiperidin-4- yl)methyl)-1,3,4-thiadiazole 399 2-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4- thiadiazole 400 2-(5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2-yl)-3-fluoro-5-(1H-pyrazol-4- yl)phenol 401 4-methoxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4- thiadiazol-2-yl)quinolin-2(1H)-one 402 4-hydroxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4- thiadiazol-2-yl)quinolin-2(1H)-one 403 3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin- 2(1H)-one 404 1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)quinolin-2(1H)-one  405¹ 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-1,3,4-thiadiazole  406¹ 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[4.5]decan-2-yl)-1,3,4- thiadiazole  407¹ (R)-(4-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)piperazin-2- yl)methanol 408 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)benzo[b]thiophene-5-carbonitrile 409 5-(3-chlorobenzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 410 5-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine  411¹ 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl(methyl)amino]pyridazin-3-yl}-5-(1H- pyrazol-4-yl)phenol  412¹ 2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol  413¹ 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3- yl}phenol 414 5-(1-methyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol  415¹ 2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol 416 5-(5-methyl-1H-pyrazol-4-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]pyridazin-3-yl}phenol 417 5-(1H-imidazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 418 5-(5-methyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol  419¹ 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H- pyrazol-1-yl)phenol 420 6-[2-methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine 421 5-(4-amino-1H-pyrazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol  422¹ 2-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol 423 5-(4-nitro-1H-pyrazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol  424¹ 5-(1H-pyrazol-4-yl)-2-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]phenol  425¹ 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol  426¹ 2-{6-[methyl(piperidin-4-yl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol  427¹ 2-[6-(piperidin-4-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol  428¹ 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyridazin-3-amine  429¹ 2-[6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol  430¹ 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyridazin-3-amine  431¹ 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 432 2-[6-(piperidin-4-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol  433¹ 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino]pyridazin-3-yl}-5-(1H-pyrazol-4- yl)phenol  434¹ 6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine 435 3-[4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine  436¹ 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol  437¹ 3-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 438 3-[4-(1-methyl-1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine  439¹ 2-[6-(2,7-diazaspiro[3.5]non-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 440 3-fluoro-4-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol 441 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-1-yl)phenol 442 N-methyl-6-(2-methyl-2H-indazol-5-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin- 3-amine 443 2-methyl-5-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}-2H-indazole 444 3-(4-chloro-2-methoxyphenyl)-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 445 N-methyl-6-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 446 6-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}imidazo[1,2-a]pyridine 447 3-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine  448¹ 3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 449 3-[5-(1-methyl-1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine  450¹ 3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 451 5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazin-3-yl}phenol 452 6-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 453 3-methoxy-4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol 454 3-[2-methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 455 4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}benzene-1,3-diol  456¹ 6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 457 2-(1H-pyrazol-4-yl)-4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}pyrimidin-5-amine  458¹ 3-[2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 459 2-[6-(2,6-diazaspiro[3.4]oct-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol  460¹ 3-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino[pyridazin-3-yl}-6-(1H-pyrazol-4- yl)pyridin-2-ol 461 6-(1H-pyrazol-4-yl)-3-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy[pyridazin-3- yl}pyridin-2-ol  462¹ N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine  463¹ N,2,2,6,6-pentamethyl-N-{5-[4-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine  464¹ 3-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine and  465¹ 6-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

In one aspect, the compound of Formula (I) or a form thereof includes a compound selected from the group consisting of:

411¹ 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl(methyl)amino]pyridazin-3-yl}-5-(1H- pyrazol-4-yl)phenol 412¹ 2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol 413¹ 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3- yl}phenol 414  5-(1-methyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 415¹ 2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol 416  5-(5-methyl-1H-pyrazol-4-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]pyridazin-3-yl}phenol 417  5-(1H-imidazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 418  5-(5-methyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 419¹ 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H- pyrazol-1-yl)phenol 420  6-[2-methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine 421  5-(4-amino-1H-pyrazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 422¹ 2-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol 423  5-(4-nitro-1H-pyrazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 424¹ 5-(1H-pyrazol-4-yl)-2-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]phenol 425¹ 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 426¹ 2-{6-[methyl(piperidin-4-yl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol 427¹ 2-[6-(piperidin-4-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 428¹ 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyridazin-3-amine 429¹ 2-[6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 430¹ 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyridazin-3-amine 431¹ 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 432  2-[6-(piperidin-4-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 433¹ 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino]pyridazin-3-yl}-5-(1H-pyrazol-4- yl)phenol 434¹ 6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine 435  3-[4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 436¹ 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol 437¹ 3-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 438  3-[4-(1-methyl-1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 439¹ 2-[6-(2,7-diazaspiro[3.5]non-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 440  3-fluoro-4-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol 441  2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-1-yl)phenol 442  N-methyl-6-(2-methyl-2H-indazol-5-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin- 3-amine 443  2-methyl-5-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}-2H-indazole 444  3-(4-chloro-2-methoxyphenyl)-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 445  N-methyl-6-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 446  6-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}imidazo[1,2-a]pyridine 447  3-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 448¹ 3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 449  3-[5-(1-methyl-1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 450¹ 3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 451  5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazin-3-yl}phenol 452  6-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 453  3-methoxy-4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol 454  3-[2-methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 455  4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}benzene-1,3-diol 456¹ 6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 457  2-(1H-pyrazol-4-yl)-4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}pyrimidin-5-amine 458¹ 3-[2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 459  2-[6-(2,6-diazaspiro[3.4]oct-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 460¹ 3-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-6-(1H-pyrazol-4- yl)pyridin-2-ol 461  6-(1H-pyrazol-4-yl)-3-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}pyridin-2-ol 462¹ N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine 463¹ N,2,2,6,6-pentamethyl-N-{5-[4-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine 464¹ 3-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine and 465¹ 6-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

Another embodiment of the use of a compound salt of Formula (I) or a form thereof includes a method of use of a compound salt of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (I) or a form thereof to the subject, selected from the group consisting of:

Cpd Name  32 2-(6-(methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino)pyridazin-3-yl)-4-   (trifluoromethyl)phenol hydrochloride  53 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-1-   yl)phenol hydrochloride  65 2-(6-piperazin-1-yl-pyridazin-3-yl)-5-1H- pyrazol-1-yl-phenol hydrochloride  82 3-(6-(piperazin-1-yl)pyridazin-3-yl)naphthalene- 2,7-diol trifluoroacetate  86 3-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin- 3-yl)naphthalene-2,7-diol trifluoroacetate  88 3-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4- yl)pyridazin-3-yl)naphthalene-2,7-diol   trifluoroacetate  89 3-(6-(piperidin-4-yl)pyridazin-3-yl)naphthalene- 2,7-diol trifluoroacetate 151 6-hydroxy-5-(6-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3- dihydro-1H-inden-1-one oxime hydrochloride 153 2-amino-6-(6-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-8H- indeno[1,2-d]thiazol-5-ol hydrochloride 154 9-(6-(methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino)pyridazin-3-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-8-ol hydrochloride 160 3-fluoro-5-(2-methoxypyridin-4-yl)-2- (6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol hydrochloride 161 4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)pyridin-2(1H)-one hydrochloride 162 4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)-1-methylpyridin-2(1H)-one hydrochloride 163 5-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)-1-methylpyridin-2(1H)-one hydrochloride 164 3-fluoro-5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6- tetramethylpiperidin-4-yl)oxy)pyridazin-3- yl)phenol hydrochloride 165 5-chloro-3-fluoro-2-(6-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol hydrochloride 166 3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol hydrochloride 167 3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino)pyridazin-3-yl)-5-(1- methyl-1H-pyrazol-4-yl)phenol hydrochloride 226 3-(1H-imidazol-1-yl)-6-(6-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol hydrochloride 227 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)quinoline-3,7-diol formate 231 7-hydroxy-1-methyl-6-(6-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-2(1H)-one hydrochloride 238 4-methoxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino)pyridazin-3-yl)quinolin- 6-ol formate 239 7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)quinoxalin-6-ol hydrochloride 254 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino)pyridazin-3-yl)-4- (tetrahydro-2H-pyran-4-yl)quinolin-7-ol formate 256 4-(dimethylamino)-6-(6-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)- quinolin-7-ol formate 281 6-hydroxy-2-methyl-7-(6-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-1(2H)-one hydrochloride 322 3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,3,4-thiadiazol-2-yl)naphthalen- 2-ol hydrobromide 342 N-methyl-5-(5-(1-methyl-1H-pyrazol-4- yl)pyridin-2-yl)-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine hydrochloride 396 3-fluoro-2-(5-((3aR,6aS)-hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4-thiadiazol-2-yl)- 5-(1H-pyrazol-4-yl)phenol dihydrochloride 405 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5- ((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-1,3,4-thiadiazole hydrochloride 406 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5- (2,7-diazaspiro[4.5]decan-2-yl)-1,3,4- thiadiazole hydrochloride 407 (R)-(4-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)- 1,3,4-thiadiazol-2-yl)piperazin-2- yl)methanol hydrochloride 411 2-{6-[8-azabicyclo[3.2.1]oct-3- yl(methyl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4- yl)phenol hydrochloride 412 2-[6-(8-azabicyclo[3.2.1]oct-3- ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 413 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6- tetramethylpiperidin-4-yl)amino]pyridazin-3- yl}phenol hydrochloride 415 2-[6-(8-azabicyclo[3.2.1]oct-3-yloxy)pyridazin- 3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 419 2-{6-[methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H- pyrazol-1-yl)phenol dihydrochloride 422 2-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4- yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol trihydrochloride 424 5-(1H-pyrazol-4-yl)-2-[6-(1,2,3,6- tetrahydropyridin-4-yl)pyridazin-3-yl]phenol trihydrochloride 425 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridin-4- yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol trihydrochloride 426 2-{6-[methyl(piperidin-4-yl)amino]pyridazin- 3-yl}-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 427 2-[6-(piperidin-4-ylamino)pyridazin-3-yl]-5- (1H-pyrazol-4-yl)phenol tetrahydrochloride 428 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]- N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine tetrahydrochloride 429 2-[6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)pyridazin- 3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 430 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine hydrochloride 431 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]- 6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine trihydrochloride 433 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3- ylamino[pyridazin-3-yl}-5-(1H-pyrazol-4- yl)phenol hydrochloride 434 6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin- 3-yl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3- amine hydrochloride 436 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin- 3-yl}-5-(1H-pyrazol-4-yl)phenol trihydrochloride 437 3-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]- 6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride 439 2-[6-(2,7-diazaspiro[3.5]non-2-yl)pyridazin- 3-yl]-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 448 3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6- [(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride 450 3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]-6- [(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride 456 6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine trihydrochloride 458 3-[2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl]- 6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine trihydrochloride 460 3-{6-[methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino]pyridazin-3-yl}-6-(1H-pyrazol-4- yl)pyridin-2-ol hydrochloride 462 N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazol- 4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine hydrochloride 463 N,2,2,6,6-pentamethyl-N-{5-[4-(1H- pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine hydrochloride 464 3-[2-(difluoromethyl)-4-(1H-pyrazol-4- yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride and 465 6-[2-(difluoromethyl)-4-(1H-pyrazol-4- yl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

In one aspect, the compound salt of Formula (I) or a form thereof includes a compound salt selected from the group consisting of:

411 2-{6-[8-azabicyclo [3.2.1]oct-3-yl(methyl)amino]pyridazin- 3-yl}-5-(1H-pyrazol-4-yl)phenol hydrochloride 412 2-[6-(8-azabicyclo[3.2.1]oct-3-ylamino)pyridazin-3- yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 413 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin- 4-yl)amino]pyridazin-3-yl}phenol hydrochloride 415 2-[6-(8-azabicyclo[3.2.1]oct-3-yloxy)pyridazin-3-yl]- 5-(1H-pyrazol-4-yl)phenol hydrochloride 419 2-{6-[methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H- pyrazol-1-yl)phenol dihydrochloride 422 2-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4- yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol trihydrochloride 424 5-(1H-pyrazol-4-yl)-2-[6-(1,2,3,6- tetrahydropyridin-4-yl)pyridazin-3-yl]phenol trihydrochloride 425 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridin-4- yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol trihydrochloride 426 2-{6-[methyl(piperidin-4-yl)amino]pyridazin- 3-yl}-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 427 2-[6-(piperidin-4-ylamino)pyridazin-3-yl]-5- (1H-pyrazol-4-yl)phenol tetrahydrochloride 428 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]- N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine tetrahydrochloride 429 2-[6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)pyridazin- 3-yl}-5-(1H-pyrazol-4-yl)phenol hydrochloride 430 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]- N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine hydrochloride 431 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]- 6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine trihydrochloride 433 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3- ylamino]pyridazin-3-yl}-5-(1H-pyrazol-4- yl)phenol hydrochloride 434 6-[2-methoxy-6-(1H-pyrazol-4- yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride 436 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin- 3-yl}-5-(1H-pyrazol-4-yl)phenol trihydrochloride 437 3-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]- 6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride 439 2-[6-(2,7-diazaspiro[3.5]non-2- yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 448 3-[5-(1H-pyrazol-4-yl)thiophen-2- yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride 450 3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]- 6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride 456 6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine trihydrochloride 458 3-[2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl]- 6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine trihydrochloride 460 3-{6-[methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino]pyridazin-3-yl}-6-(1H-pyrazol-4- yl)pyridin-2-ol hydrochloride 462 N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazol- 4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine hydrochloride 463 N,2,2,6,6-pentamethyl-N-{5-[4-(1H-pyrazol- 4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine hydrochloride 464 3-[2-(difluoromethyl)-4-(1H-pyrazol-4- yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride and 465 6-[2-(difluoromethyl)-4-(1H-pyrazol-4- yl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

Another embodiment of the present description includes a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof to the subject.

Another embodiment of the present description includes a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (I) or a form thereof to the subject.

Another embodiment of the present description includes a use of the compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof to the subject.

Another embodiment of the present description includes a use of the compound salt of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (I) or a form thereof to the subject.

Chemical Definitions

As used herein, the term “C₁₋₄alkyl” generally refers to saturated hydrocarbon radicals having from one to four carbon atoms in a straight or branched chain configuration, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like. In some embodiments, C₁₋₄alkyl includes C₁₋₃alkyl, C₁₋₂alkyl, and the like. A C₁₋₄alkyl radical may be optionally substituted where allowed by available valences.

As used herein, the term “C₂₋₆alkenyl” generally refers to partially unsaturated hydrocarbon radicals having from two to five carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, without limitation, ethenyl, allyl, propenyl and the like. In some embodiments, C₂₋₆alkenyl includes C₂₋₄alkenyl, C₂₋₃alkenyl, and the like. A C₂₋₆alkenyl radical may be optionally substituted where allowed by available valences.

As used herein, the term “C₁₋₄alkoxy” generally refers to saturated hydrocarbon radicals having from one to four carbon atoms in a straight or branched chain configuration of the formula: —O—C₁₋₄alkyl, including, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. In some embodiments, C₁₋₄alkoxy includes C₁₋₃alkoxy, C₁₋₂alkoxy and the like. A C₁₋₄alkoxy radical may be optionally substituted where allowed by available valences.

As used herein, the term “C₃₋₁₄cycloalkyl” generally refers to a saturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, tetrahydro-naphthalenyl and the like. In some embodiments, C₃₋₁₄cycloalkyl includes C₃₋₁₀cycloalkyl, C₃₋₈cycloalkyl, C₃₋₇cycloalkyl, C₅₋₈cycloalkyl, C₉₋₁₀cycloalkyl and the like. A C₃₋₁₄cycloalkyl radical may be optionally substituted where allowed by available valences.

As used herein, the term “C₃₋₁₄cycloalkenyl” generally refers to a partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon radical having one or more chemically stable carbon-carbon double bonds therein, including, without limitation, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like. In some embodiments, C₃₋₁₄cycloalkenyl includes C₃₋₇cycloalkenyl, C₃₋₈cycloalkenyl, C₅₋₈cycloalkenyl, C₃₋₁₀cycloalkenyl and the like. A C₃₋₁₄cycloalkenyl radical may be optionally substituted where allowed by available valences.

As used herein, the term “aryl” generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like. An aryl radical may be optionally substituted where allowed by available valences.

As used herein, the term “heteroaryl” generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom, including, without limitation, furanyl, thienyl (also referred to as thiophenyl), pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, 9H-purinyl, quinoxalinyl, isoindolyl, quinolinyl, isoquinolinyl, quinazolinyl, acridinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, imidazo[5,1-a]isoquinolinyl, 1,4-dihydroindeno[1,2-c]-1H-pyrazolyl, 2,3-dihydro-1H-inden-1-one, 2,3-dihydro-1H-indenyl, 3,4-dihydroquinolin-2(1H)-one, 5,6-dihydroimidazo[5,1-a]isoquinolinyl, 8H-indeno[1,2-d]thiazolyl, benzo[c][1,2,5]oxadiazolyl, benzo[d]oxazol-2(3H)-one, quinolin-2(1H)-one, quinazolin-4(1H)-one, quinazoline-2,4(1H,3H)-dione, benzo-[d]oxazolyl, pyrazolo[1,5-a]pyridinyl, and the like. A heteroaryl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.

As used herein, the term “heterocyclyl” generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including, without limitation, oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, dihydropyrazolyl, pyrazolinyl, pyrazolidinyl, dihydroimidazolyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, dihydro-2H-pyranyl, dihydro-pyridinyl, tetrahydro-pyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydro-pyridinyl, dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, 1,4,5,6-tetrahydropyrimidinyl, dihydro-pyrazinyl, tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl, tetrahydro-benzothienyl, dihydro-benzimidazolyl, tetrahydro-benzimidazolyl, dihydro-benzooxazolyl, 2,3-dihydrobenzo[d]oxazolyl, tetrahydro-benzooxazolyl, dihydro-benzooxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, tetrahydro-benzooxazinyl, benzo[1,3]dioxolyl, benzo[1,4]dioxanyl, dihydro-purinyl, tetrahydro-purinyl, dihydro-quinolinyl, tetrahydro-quinolinyl, 1,2,3,4-tetrahydroquinolinyl, dihydro-isoquinolinyl, 3,4-dihydroisoquinolin-(1H)-yl, tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, dihydro-quinazolinyl, tetrahydro-quinazolinyl, dihydro-quinoxalinyl, tetrahydro-quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dioxolanyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-imidazolyl, tetrahydro-2H-pyranyl, hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-(4aH)-yl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, (cis)-octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-1H-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro-1H-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-1H-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9-tetrahydro-1H-carbazolyl, 1,2,3,4-tetrahydropyrazino[1,2-a]indolyl, 2,3-dihydro-1H-pyrrolo[1,2-a]indolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4S,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, 1,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-1H-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptenyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.0]hexanyl, (1R,5S)-3-azabicyclo[3.1.0]hexanyl, (1S,5R)-3-azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 3,6-diazabicyclo[3.2.1]octyl, 1,4-dihydroindeno[1,2-c]pyrazolyl, dihydropyranyl, dihydropyridinyl, dihydroquinolinyl, 8H-indeno[1,2-d]thiazolyl, tetrahydroimidazo[1,2-a]pyridinyl, pyridin-2(1H)-one, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl and the like. A heterocyclyl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.

As used herein, the term “C₂₋₄alkenyl-amino-carbonyl” refers to a radical of the formula: —C(═O)—NH—C₂₋₄alkenyl.

As used herein, the term “C₁₋₄alkoxy-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-O—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkoxy-carbonyl” refers to a radical of the formula: —C(═O)—O—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkoxy-carbonyl-amino” refers to a radical of the formula: —NH—C(═O)—O—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkoxy-carbonyl-amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-NH—C(═O)—O—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkyl-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkyl)₂-amino” refers to a radical of the formula: —N(C₁₋₄alkyl)₂.

As used herein, the term “C₁₋₄alkyl-amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-NH—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkyl)₂-amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-N(C₁₋₄alkyl)₂.

As used herein, the term “C₁₋₄alkyl-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-NH—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkyl)₂-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-N(C₁₋₄alkyl)₂.

As used herein, the term “C₁₋₄alkyl-amino-carbonyl” refers to a radical of the formula: —C(═O)—NH—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkyl)₂-amino-carbonyl” refers to a radical of the formula: —C(═O)—N(C₁₋₄alkyl)₂.

As used herein, the term “C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-C(═O)—NH—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkyl)₂-amino-carbonyl-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-C(═O)—N(C₁₋₄alkyl)₂.

As used herein, the term “C₁₋₄alkyl-carbonyl” refers to a radical of the formula: —C(═O)—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkyl-carbonyl-amino” refers to a radical of the formula: —NH—C(═O)—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-NH—C(═O)—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-NH—C(═O)—C₁₋₄alkyl.

As used herein, the term “amino” refers to a radical of the formula: —NH₂.

As used herein, the term “amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-NH₂.

As used herein, the term “amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-NH₂.

As used herein, the term “amino-carbonyl” refers to a radical of the formula: —C(═O)—NH₂.

As used herein, the term “cyano” refers to a radical of the formula: —CN.

As used herein, the term “C₃₋₇cycloalkyl-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-C₃₋₇cycloalkyl.

As used herein, the term “halo-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-halo, wherein C₁₋₄alkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms. In some embodiments, halo-C₁₋₄alkoxy includes halo-C₁₋₆alkoxy, halo-C₁₋₄alkoxy and the like.

As used herein, the term “halo-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-halo, wherein C₁₋₄alkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms. In some embodiments, halo-C₁₋₄alkyl includes halo-C₁₋₆alkyl, halo-C₁₋₄alkyl and the like.

As used herein, the term “heteroaryl-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-heteroaryl.

As used herein, the term “heteroaryl-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-heteroaryl.

As used herein, the term “heteroaryl-C₁₋₄alkyl-amino-carbonyl” refers to a radical of the formula: —C(═O)—NH—C₁₋₄alkyl-heteroaryl.

As used herein, the term “heteroaryl-C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-C(═O)—NH—C₁₋₄alkyl-heteroaryl.

As used herein, the term “heteroaryl-C₁₋₄alkyl-carbonyl-amino” refers to a radical of the formula: —NH—C(═O)—C₁₋₄alkyl-heteroaryl.

As used herein, the term “heteroaryl-C₁₋₄alkyl-carbonyl-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-NH—C(═O)—C₁₋₄alkyl-heteroaryl.

As used herein, the term “heterocyclyl-C₁₋₄alkoxy” refers to a radical of the formula: —C₁₋₄alkoxy-heterocyclyl.

As used herein, the term “heterocyclyl-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-heterocyclyl.

As used herein, the term “hydroxyl” refers to a radical of the formula: —OH.

As used herein, the term “hydroxyl-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-OH, wherein C₁₋₄alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxy radicals.

As used herein, the term “hydroxyl-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-OH, wherein C₁₋₄alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxy radicals.

As used herein, the term “hydroxyl-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-OH, wherein C₁₋₄alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.

As used herein, the term “hydroxyl-imino” refers to the ═NOH radical of the formula: C(═NOH).

As used herein, the term “oxo” refers to the radical of the formula: C═O.

As used herein, the term “phenyl-C₁₋₄alkoxy” refers to a radical of the formula: —C₁₋₄alkoxy-phenyl.

As used herein, the term “substituent” means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances one or more substituents having a double bond (e.g., “oxo” or “═O”) as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure of Formula (I). A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.

As used herein, the term “and the like,” with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that could be expected by one skilled in the art include, without limitation, isomers (including chain, branching or positional structural isomers), hydration of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations where allowed by available valences which result in a stable compound.

For the purposes of this description, where one or more substituent variables for a compound of Formula (I) or a form thereof encompass functionalities incorporated into a compound of Formula (I), each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.

As used herein, the terms “independently selected,” or “each selected” refer to functional variables in a substituent list that may occur more than once on the structure of Formula (I), the pattern of substitution at each occurrence is independent of the pattern at any other occurrence.

Further, the use of a generic substituent variable on any formula or structure for a compound described herein is understood to include the replacement of the generic substituent with species substituents that are included within the particular genus, e.g., aryl may be replaced with phenyl or naphthalenyl and the like, and that the resulting compound is to be included within the scope of the compounds described herein.

As used herein, the terms “each instance of” or “in each instance, when present,“when used preceding a phrase such as” . . . C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₁₄alkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl, heteroaryl-C₁₋₄alkyl, heterocyclyl and heterocyclyl-C₁₋₄alkyl,” are intended to refer to the C₃₋₁₄cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems when each are present either alone or as a substituent.

As used herein, the term “optionally substituted” means optional substitution with the specified substituent variables, groups, radicals or moieties.

Compound Forms

As used herein, the term “form” means a compound of Formula (I) having a form selected from the group consisting of a free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

In certain embodiments described herein, the form of the compound of Formula (I) is a free acid, free base or salt thereof.

In certain embodiments described herein, the form of the compound of Formula (I) is a salt thereof.

In certain embodiments described herein, the form of the compound of Formula (I) is an isotopologue thereof.

In certain embodiments described herein, the form of the compound of Formula (I) is a stereoisomer, racemate, enantiomer or diastereomer thereof.

In certain embodiments described herein, the form of the compound of Formula (I) is a tautomer thereof.

In certain embodiments described herein, the form of the compound of Formula (I) is a pharmaceutically acceptable form.

In certain embodiments described herein, the compound of Formula (I) or a form thereof is isolated for use.

As used herein, the term “isolated” means the physical state of a compound of Formula (I) or a form thereof after being isolated and/or purified from a synthetic process (e.g., from a reaction mixture) or natural source or combination thereof according to an isolation or purification process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterized by standard analytical techniques described herein or well known to the skilled artisan.

As used herein, the term “protected” means that a functional group in a compound of Formula (I) or a form thereof is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxy, phenol, amino and carboxylic acid.

Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. In certain instances, the protecting group may also be a polymer resin, such as a Wang resin or a 2-chlorotrityl-chloride resin. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein. It will also be appreciated by those skilled in the art, although such protected derivatives of compounds described herein may not possess pharmacological activity as such, they may be administered to a subject and thereafter metabolized in the body to form compounds described herein which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All prodrugs of compounds described herein are included within the scope of the use described herein.

As used herein, the term “prodrug” means a form of an instant compound (e.g., a drug precursor) that is transformed in vivo to yield an active compound of Formula (I) or a form thereof. The transformation may occur by various mechanisms (e.g., by metabolic and/or non-metabolic chemical processes), such as, for example, by hydrolysis and/or metabolism in blood, liver and/or other organs and tissues. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

In one example, when a compound of Formula (I) or a form thereof contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a functional group such as alkyl and the like. In another example, when a compound of Formula (I) or a form thereof contains a hydroxyl functional group, a prodrug form can be prepared by replacing the hydrogen atom of the hydroxyl with another functional group such as alkyl, alkylcarbonyl or a phosphonate ester and the like. In another example, when a compound of Formula (I) or a form thereof contains an amine functional group, a prodrug form can be prepared by replacing one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl. Pharmaceutically acceptable prodrugs of compounds of Formula (I) or a form thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters, phosphonate esters and mono-, di- or triphosphate esters or alkyl substituents, where appropriate. As described herein, it is understood by a person of ordinary skill in the art that one or more of such substituents may be used to provide a compound of Formula (I) or a form thereof as a prodrug.

One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to embrace both solvated and unsolvated forms.

As used herein, the term “solvate” means a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. As used herein, “solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

As used herein, the term “hydrate” means a solvate wherein the solvent molecule is water.

The compounds of Formula (I) can form salts, which are intended to be included within the scope of this description. Reference to a compound of Formula (I) or a form thereof herein is understood to include reference to salt forms thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula (I) or a form thereof contains both a basic moiety, such as, without limitation an amine moiety, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein.

The term “pharmaceutically acceptable salt(s)”, as used herein, means those salts of compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of the Formula (I) may be formed, for example, by reacting a compound of Formula (I) or a form thereof with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in compounds described herein. Embodiments of acid addition salts include, and are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate salts and the like. Certain embodiments of acid addition salts include chloride, dichloride, trichloride, bromide, acetate, formate or trifluoroacetate salts.

Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium and zinc salts.

All such acid salts and base salts are intended to be included within the scope of pharmaceutically acceptable salts as described herein. In addition, all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this description.

Compounds of Formula (I) and forms thereof, may further exist in a tautomeric form. All such tautomeric forms are contemplated and intended to be included within the scope of the compounds of Formula (I) or a form thereof as described herein.

The compounds of Formula (I) or a form thereof may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. The present description is intended to include all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures.

The compounds described herein may include one or more chiral centers, and as such may exist as racemic mixtures (R/S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (when one chiral center is present). In one embodiment, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another embodiment, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of skill in the art will recognize, when more than one chiral center is present, the compounds described herein may also exist as a (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature Recommendations.

As used herein, the term “substantially pure” refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.

In one aspect of the description, a compound of Formula (I) or a form thereof is a substantially pure (S) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

In one aspect of the description, a compound of Formula (I) or a form thereof is a substantially pure (R) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

As used herein, a “racemate” is any mixture of isometric forms that are not “enantiomerically pure”, including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20.

In addition, the present description embraces all geometric and positional isomers. For example, if a compound of Formula (I) or a form thereof incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the description. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by use of chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this description.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this description, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described supra.

The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or isotopologues of the instant compounds.

The term “isotopologue” refers to isotopically-enriched compounds described herein which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁵Cl and ³⁶Cl, respectively, each of which are also within the scope of this description.

Certain isotopically-enriched compounds described herein (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.

Polymorphic crystalline and amorphous forms of the compounds of Formula (I) and of the salts, solvates, hydrates, esters and prodrugs of the compounds of Formula (I) are further intended to be included in the present description.

Compound Uses

The present description relates to a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound or a form thereof to the subject.

The present description further relates to use of the compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof.

The present description further relates to use of the compound of Formula (I) or a form thereof having activity toward HD.

The present description further relates to use of the compound of Formula (I) or a form thereof in a combination therapy to provide additive or synergistic activity, thus enabling the development of a combination product for treating or ameliorating HD.

In addition to monotherapeutic use, the instant compounds are useful in a combination therapy with current standard of agents, having additive or synergistic activity with one or more known agents.

A combination therapy comprising compounds described herein in combination with one or more known drugs may be used to treat HD regardless of whether HD is responsive to the known drug.

Embodiments of the present description include the use of a compound of Formula (I) or a form thereof in a combination therapy for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof and an effective amount of one or more agent(s).

Embodiments of the present description include the use of a compound of Formula (I) or a form thereof in a combination therapy for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof and an effective amount of one or more agent(s).

In an embodiment of a use or method provided herein, compounds of Formula (I) or a form thereof used in combination with one or more additional agents can be administered to a subject or contacted with a subject or patient cell(s) prior to, concurrently with, or subsequent to administering to the subject or patient or contacting the cell with an additional agent(s). A compound(s) of Formula (I) or a form thereof and an additional agent(s) can be administered to a subject or contacted with a cell in single composition or different compositions. In a specific embodiments, a compound(s) of Formula (I) or a form thereof is used in combination with gene therapy to inhibit HTT expression (using, e.g., viral delivery vectors) or the administration of another small molecule HTT inhibitor. In another specific embodiment, a compound(s) of Formula (I) or a form thereof are used in combination with cell replacement using differentiated non-mutant HTT stem cells. In another specific embodiment, a compound(s) of Formula (I) or a form thereof are used in combination with cell replacement using differentiated HTT stem cells.

In one embodiment, provided herein is the use of compounds of Formula (I) or a form thereof in combination with supportive standard of care therapies, including palliative care.

An embodiment of the present description includes the use of a compound of Formula (I) or a form thereof in the preparation of a kit comprising the compound of Formula (I) or a form thereof and instructions for administering an effective amount of the compound of Formula (I) or a form thereof and an effective amount of one or more agent(s) in a combination therapy for treating or ameliorating HD in a subject in need thereof.

Accordingly, the present description relates to use of a compound of Formula (I) or a form thereof for treating or ameliorating HD. In accordance with the use of the present description, compounds that are useful in selectively treating or ameliorating HD, have been identified and use of these compounds for treating or ameliorating HD has been provided.

One embodiment of the use of the present description relates to use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof to the subject.

One embodiment of the use of the present description relates to a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound to the subject.

An embodiment of the use of the present description relates to a method of use of a compound of Formula (I) or a form thereof for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound to the subject.

An embodiment of the use of the present description relates to use of a compound of Formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.

An embodiment of the use of the present description relates to use of a compound of Formula (I) or a form thereof in the preparation of a kit comprising the compound of Formula (I) or a form thereof and instructions for administering the compound for treating or ameliorating HD in a subject in need thereof.

In one respect, for each of such embodiments, the subject is treatment naive. In another respect, for each of such embodiments, the subject is not treatment naive.

As used herein, the term “treating” refers to: (i) preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder and/or condition; (ii) inhibiting a disease, disorder or condition, i.e., arresting the development thereof; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.

As used herein, the term “subject” refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires oxygen and organic food. Nonlimiting examples include members of the human, primate, equine, porcine, bovine, murine, rattus, canine and feline specie. In some embodiments, the subject is a mammal or a warm-blooded vertebrate animal. In other embodiments, the subject is a human. As used herein, the term “patient” may be used interchangeably with “subject” and “human”.

As used herein, the terms “effective amount” or “therapeutically effective amount” mean an amount of compound of Formula (I) or a form, composition or medicament thereof effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect in a subject in need thereof.

The dose administered to achieve an effective target plasma concentration may also be administered based upon the weight of the subject or patient. Doses administered on a weight basis may be in the range of about 0.001 mg/kg/day to about 3500 mg/kg/day, or about 0.001 mg/kg/day to about 3000 mg/kg/day, or about 0.001 mg/kg/day to about 2500 mg/kg/day, or about 0.001 mg/kg/day to about 2000 mg/kg/day, or about 0.001 mg/kg/day to about 1500 mg/kg/day, or about 0.001 mg/kg/day to about 1000 mg/kg/day, or about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.001 mg/kg/day to about 250 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day, or about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 50 mg/kg/day, or about 0.001 mg/kg/day to about 40 mg/kg/day, or about 0.001 mg/kg/day to about 30 mg/kg/day, or about 0.001 mg/kg/day to about 20 mg/kg/day, or about 0.001 mg/kg/day to about 10 mg/kg/day, or about 0.01 mg/kg/day to about 2000 mg/kg/day, or about 0.01 mg/kg/day to about 1500 mg/kg/day, or about 0.01 mg/kg/day to about 1000 mg/kg/day, or about 0.01 mg/kg/day to about 600 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 300 mg/kg/day, or about 0.015 mg/kg/day to about 200 mg/kg/day, or about 0.02 mg/kg/day to about 100 mg/kg/day, or about 0.025 mg/kg/day to about 100 mg/kg/day, or about 0.03 mg/kg/day to about 100 mg/kg/day, wherein said amount is orally administered once (once in approximately a 24 hour period), twice (once in approximately a 12 hour period) or thrice (once in approximately an 8 hour period) daily according to subject weight.

In certain embodiments, the effective amount will be in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.1 mg to about 500 mg/kg/day, or about 1.0 mg/day to about 500 mg/kg/day, in single, divided, or a continuous dose for a patient or subject having a weight in a range of between about 40 to about 200 kg (which dose may be adjusted for patients or subjects above or below this range, particularly children under 40 kg). The typical adult subject is expected to have a median weight in a range of about 70 kg.

In another embodiment, where daily doses are adjusted based upon the weight of the subject or patient, compounds described herein may be formulated for delivery at about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 3.0, 5.0, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400 or 500 mg/kg/day. Daily doses adjusted based upon the weight of the subject or patient may be administered as a single, divided, or continuous dose. In embodiments where a dose of compound is given more than once per day, the dose may be administered twice, thrice, or more times per day.

Within the scope of the present description, the “effective amount” of a compound of Formula (I) or a form thereof for use in the manufacture of a medicament, for use in the preparation of a pharmaceutical kit or in a method of use for treating or ameliorating HD in a subject in need thereof is intended to include an amount in a range of from about 0.001 mg/kg/day to about 3500 mg/kg/day, or about 0.001 mg/kg/day to about 3000 mg/kg/day, or about 0.001 mg/kg/day to about 2500 mg/kg/day, or about 0.001 mg/kg/day to about 2000 mg/kg/day, or about 0.001 mg/kg/day to about 1500 mg/kg/day, or about 0.001 mg/kg/day to about 1000 mg/kg/day, or about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.001 mg/kg/day to about 250 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day, or about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 50 mg/kg/day, or about 0.001 mg/kg/day to about 40 mg/kg/day, or about 0.001 mg/kg/day to about 30 mg/kg/day, or about 0.001 mg/kg/day to about 20 mg/kg/day, or about 0.001 mg/kg/day to about 10 mg/kg/day, or about 0.01 mg/kg/day to about 2000 mg/kg/day, or about 0.01 mg/kg/day to about 1500 mg/kg/day, or about 0.01 mg/kg/day to about 1000 mg/kg/day, or about 0.01 mg/kg/day to about 600 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 300 mg/kg/day, or about 0.015 mg/kg/day to about 200 mg/kg/day, or about 0.02 mg/kg/day to about 100 mg/kg/day, or about 0.025 mg/kg/day to about 100 mg/kg/day, or about 0.03 mg/kg/day to about 100 mg/kg/day, wherein said amount is administered once (once in approximately a 24 hour period; i.e., “q.d.”), twice (once in approximately a 12 hour period; i.e., “b.i.d.” or “q.12h”), thrice (once in approximately an 8 hour period; i.e., “t.i.d.” or “q.8h”), or four times (once in approximately a 6 hour period; i.e., “q.d.s.”, “q.i.d.” or “q.6h”) daily according to subject weight.

Such amounts may further include an amount in a range of from about 0.001 mg to about 3500 mg administered daily; 0.001 mg to about 3000 mg administered daily; 0.001 mg to about 2500 mg administered daily; 0.001 mg to about 2000 mg administered daily; 0.001 mg to about 1500 mg administered daily; 0.001 mg to about 1000 mg administered daily; 0.001 mg to about 500 mg administered daily; 0.001 mg to about 250 mg administered daily; 1.0 mg to about 3500 mg administered daily; 1.0 mg to about 1500 mg administered daily; 1.0 mg to about 1000 mg administered daily; 10.0 mg to about 600 mg administered daily; 0.5 mg to about 2000 mg administered daily; or, an amount in a range of from about 5.0 mg to about 300 mg administered daily.

For example, the effective amount may be the amount required to treat HD in a subject or, more specifically, in a human. The effective amount for a subject will depend upon various factors, including the subject's body weight, size and health. Effective amounts for a given patient can be determined by routine experimentation that is within the skill and judgment of the clinician.

For any compound, the effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as a mouse, chimpanzee, marmoset or tamarin animal model. Relevant animal models may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED₅₀ (the dose therapeutically effective in 50% of the population) and LD₅₀ (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is therapeutic index, and can be expressed as the ratio, LD₅₀/ED₅₀. In some embodiments, the effective amount is such that a large therapeutic index is achieved. In further embodiments, the dosage is within a range of circulating concentrations that include an ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

More specifically, the concentration-biological effect relationships observed with regard to a compound of Formula (I) or a form thereof indicate a target plasma concentration ranging from approximately 0.001 μg/mL to approximately 50 μg/mL, from approximately 0.01 μg/mL to approximately 20 μg/mL, from approximately 0.05 μg/mL to approximately 10 μg/mL, or from approximately 0.1 μg/mL to approximately 5 μg/mL. To achieve such plasma concentrations, the compounds described herein may be administered at doses that vary, such as, for example, without limitation, from 0.1 ng to 10,000 mg, depending upon the route of administration in single, divided, or continuous doses for a patient weighing between about 10 to about 100 kg (which dose may be adjusted for patients within this weight range, particularly for children under 40 kg).

The exact dosage will be determined by the practitioner, in light of factors related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, ethnicity, age, weight, gender, diet, time of day and frequency of administration, drug combination(s), reaction sensitivities, experience with other therapies, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 2, 3 or 4 days, once every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

The compounds and compositions described herein may be administered to the subject via any drug delivery route known in the art. Nonlimiting examples include oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, and pulmonary routes of administration.

In one aspect, provided herein are methods for modulating the amount of HTT (huntingtin protein), comprising contacting a human cell with a compound of Formula (I) or a form thereof. In a specific embodiment, provided herein are methods for modulating the amount of HTT, comprising contacting a human cell with a compound of Formula (I) or a form thereof that modulates the expression of HTT. The human cell can be contacted with a compound of Formula (I) or a form thereof in vitro, or in vivo, e.g., in a non-human animal or in a human. In a specific embodiment, the human cell is from or in a human. In another specific embodiment, the human cell is from or in a human with HD. In another specific embodiment, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in a loss of HTT expression and/or function. In another embodiment, the human cell is from a human with HD. In another embodiment, the human cell is in a human with HD. In one embodiment, the compound is a form of the compound of Formula (I).

In a specific embodiment, provided herein is a method for enhancing the inhibition of mutant HTT transcribed from the Htt gene, comprising contacting a human cell with a compound of Formula (I) or a form thereof. The human cell can be contacted with a compound of Formula (I) or a form thereof in vitro, or in vivo, e.g., in a non-human animal or in a human. In a specific embodiment, the human cell is from or in a human. In another specific embodiment, the human cell is from or in a human with HD. In another specific embodiment, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in a loss of wild-type “normal” HTT expression and/or function. In another embodiment, the human cell is from a human with HD. In another embodiment, the human cell is in a human with HD. In one embodiment, the compound is a form of the compound of Formula (I).

In another aspect, provided herein is a method for modulating the inhibition of mutant HTT transcribed from the Htt gene, comprising administering to a non-human animal model for HD a compound of Formula (I) or a form thereof. In a specific embodiment, provided herein is a method for modulating the inhibition of mutant HTT transcribed from the Htt gene, comprising administering to a non-human animal model for HD a compound of Formula (I) or a form thereof. In a specific embodiment, the compound is a form of the compound of Formula (I).

In another aspect, provided herein is a method for decreasing the amount of mutant HTT, comprising contacting a human cell with a compound of Formula (I) or a form thereof. In a specific embodiment, provided herein is a method for decreasing the amount of mutant HTT, comprising contacting a human cell with a compound of Formula (I) that inhibits the transcription of mutant HTT (huntingtin mRNA) from the Htt gene. In another specific embodiment, provided herein is a method for decreasing the amount of HTT, comprising contacting a human cell with a compound of Formula (I) that inhibits the expression of mutant HTT transcribed from the Htt gene. The human cell can be contacted with a compound of Formula (I) or a form thereof in vitro, or in vivo, e.g., in a non-human animal or in a human. In a specific embodiment, the human cell is from or in a human. In another specific embodiment, the human cell is from or in a human with HD. In another specific embodiment, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in a loss of HTT expression and/or function. In another embodiment, the human cell is from a human with HD. In another embodiment, the human cell is in a human with HD. In one embodiment, the compound is a form of the compound of Formula (I).

In certain embodiments, treating or ameliorating HD with a compound of Formula (I) or a form thereof (alone or in combination with an additional agent) has a therapeutic effect and/or beneficial effect. In a specific embodiment, treating HD with a compound of Formula (I) or a form thereof (alone or in combination with an additional agent) results in one, two or more of the following effects: (i) reduces or ameliorates the severity of HD; (ii) delays onset of HD; (iii) inhibits the progression of HD; (iv) reduces hospitalization of a subject; (v) reduces hospitalization length for a subject; (vi) increases the survival of a subject; (vii) improves the quality of life for a subject; (viii) reduces the number of symptoms associated with HD; (ix) reduces or ameliorates the severity of a symptom(s) associated with HD; (x) reduces the duration of a symptom associated with HD; (xi) prevents the recurrence of a symptom associated with HD; (xii) inhibits the development or onset of a symptom of HD; and/or (xiii) inhibits of the progression of a symptom associated with HD.

Metabolites of the Compounds

Also included within the scope of the present description are the use of in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the description includes the use of compounds produced by a process comprising contacting a compound described herein with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof.

Such products typically are identified by preparing a radio-labeled isotopologue (e.g., ¹⁴C or ³H) of a compound described herein, administering the radio-labeled compound in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as a rat, mouse, guinea pig, dog, monkey or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours), and identifying the metabolic conversion products from urine, bile, blood or other biological samples. The conversion products are easily isolated since they are “radiolabeled” by virtue of being isotopically-enriched (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds described herein even if they possess no biological activity of their own.

Pharmaceutical Compositions

Embodiments of the present description include the use of a compound of Formula (I) or a form thereof in a pharmaceutical composition for treating or ameliorating HD in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipient(s).

An embodiment of the present description includes the use of a pharmaceutical composition of the compound of Formula (I) or a form thereof in the preparation of a kit comprising the pharmaceutical composition of the compound of Formula (I) or a form thereof and instructions for administering the compound for treating or ameliorating HD in a subject in need thereof.

As used herein, the term “composition” means a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The pharmaceutical composition may be formulated to achieve a physiologically compatible pH, ranging from about pH 3 to about pH 11. In some embodiments, the pharmaceutical composition is formulated to achieve a pH of from about pH 3 to about pH 7. In other embodiments, the pharmaceutical composition is formulated to achieve a pH of from about pH 5 to about pH 8.

The term “pharmaceutically acceptable excipient” refers to an excipient for administration of a pharmaceutical agent, such as the compounds described herein. The term refers to any pharmaceutical excipient that may be administered without undue toxicity.

Pharmaceutically acceptable excipients may be determined in part by the particular composition being administered, as well as by the particular mode of administration and/or dosage form.

Nonlimiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, etc. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions for the instant compounds described herein (see, e.g., Remington's Pharmaceutical Sciences).

Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive antibodies. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose (e.g., hydroxypropylmethylcellulose, also known as HPMC), stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions described herein may be formulated in any form suitable for the intended use described herein. Suitable formulations for oral administration include solids, liquid solutions, emulsions and suspensions, while suitable inhalable formulations for pulmonary administration include liquids and powders. Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids which can be reconstituted with a physiologically compatible solvent prior to administration.

When intended for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents, and preserving agents, in order to provide a palatable preparation.

Pharmaceutically acceptable excipients suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin, or olive oil.

In other embodiments, pharmaceutical compositions described herein may be formulated as suspensions comprising a compound of Formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipient(s) suitable for the manufacture of a suspension. In yet other embodiments, pharmaceutical compositions described herein may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of one or more excipient(s).

Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

The pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

Additionally, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propanediol.

The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The compounds described herein may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but generally soluble in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides and in propylene glycol esters of medium-chain fatty acids. Thus, contemplated in the description are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.

In some embodiments, the compound described herein is formulated for oral administration in a lipid-based composition suitable for low solubility compounds. Lipid-based formulations can generally enhance the oral bioavailability of such compounds. As such, pharmaceutical compositions described herein may comprise a effective amount of a compound of Formula (I) or a form thereof, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polysorbate 20 or 80 (also referred to as Tween® 20 or Tween® 80, respectively) or polyoxyl 40 hydrogenated castor oil.

In other embodiments, the bioavailability of low solubility compounds may be enhanced using particle size optimization techniques including the preparation of nanoparticles or nanosuspensions using techniques known to those skilled in the art. The compound forms present in such preparations include amorphous, partially amorphous, partially crystalline or crystalline forms.

In alternative embodiments, the pharmaceutical composition may further comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin. Nonlimiting examples of cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin, and hydroxypropyl-β-cyclodextrin (HPBC). In some embodiments, the pharmaceutical composition further comprises HPBC in a range of from about 0.1% to about 20%, from about 1% to about 15%, or from about 2.5% to about 10%. The amount of solubility enhancer employed may depend on the amount of the compound in the composition.

Preparation of Compounds

Compounds provided herein can be prepared by those skilled in the art, such as, by the synthetic methods set forth in International Application Publication Number WO2014/028459 A1, published Feb. 20, 2014, International Application Publication Number WO2014/116845 A1, published Jul. 31, 2014, and International Application Publication Number WO2015/017589 A1, published Feb. 5, 2015, each of which are herein incorporated by reference.

General Schemes

The following reaction schemes illustrate methods to make compounds described herein. It is understood that one skilled in the art would be able to make these compounds by similar methods or by methods known to one skilled in the art.

In general, starting components and reagents may be commercially obtained from various sources such as commercial vendors, synthesized according to methodology known to those skilled in the art, or prepared as described herein. It is understood that in the following description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds.

In general, compounds of Formula (I) described herein can be synthesized following the general procedure for Scheme 1.

General Procedure for Scheme 1

The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, the compounds described herein are prepared in the above reaction Scheme 1 as follows: a halogenated Compound 1a (wherein Hal is a halogen selected from bromine or chlorine) is reacted with a Compound 1b (wherein H is a reactive hydrogen atom in an amine or alcohol X functional group, wherein X and B for a compound of Formula (I) are as described herein) using a displacement or a metal-mediated cross coupling reaction, such as a Buchwald reaction, to provide an intermediate Compound 1c. Compound 1c is carried forward and reacted with a boronate acid or boronate ester Compound 1d (where B represents a boron atom, R represents a an acid or ester functional group or, when taken together with boron, form a ring system and A for a compound of Formula (I) is as described herein) using a transition metal-mediated cross coupling reaction, such as a Suzuki reaction, to provide a Compound of Formula (I).

In a complementary manner, compounds of Formula (I) may also be synthesized in reverse order wherein the boronate Compound 1d is reacted first with Compound 1a followed by reaction of the intermediate with amine Compound 1b. Other variations representing different combinations for substituting either or both boronate Compound 1d and amine Compound 1b on Compound 1a are intended to be included within the scope of the synthetic methodologies described herein.

SPECIFIC EXAMPLES

To assist in understanding the present description, the following specific examples are included. The experiments relating to this description should not, of course, be construed as specifically limiting the description and such variations of the description, now known or later developed, which would be within the purview of one skilled in the art are considered to fall within the scope of the description as described herein and hereinafter claimed.

Other than in the working examples, unless indicated to the contrary, all numbers expressing quantities of materials, reagents, reaction conditions, experimental data, and so forth used in the specification and claims are to be understood as being modified by the term “about”. Accordingly, all such numbers represent approximations that may vary depending upon the desired properties sought to be obtained by a reaction or as a result of variable experimental conditions. Therefore, within an expected range of experimental reproducibility, the term “about” in the context of the resulting data, refers to a range for data provided that may vary according to a standard deviation from the mean. As well, for experimental results provided, the resulting data may be rounded up or down to present data consistently, without loss of significant figures. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques.

While the numerical ranges and parameters setting forth the broad scope of the description are approximations, the numerical values set forth in the working examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

The column chromatography system used for product purification was an ISCO CombiFlash™ brand chromatography system (manufactured by Teledyne Isco).

SYNTHETIC EXAMPLES

Greater details of the present description are provided with reference to the following non-limiting examples, which are offered to more fully illustrate the description, but are not to be construed as limiting the scope thereof. The examples illustrate the preparation of certain compounds described herein, and the testing of these compounds in vitro and/or in vivo. Those of skill in the art will understand that the techniques described in these examples represent techniques described by the inventors to function well in the practice of the description, and as such constitute preferred modes for the practice thereof. However, those of skill in the art should appreciate in light of the present disclosure that many changes can be made to the specific methods that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the description.

As used above, and throughout this description, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

Abbreviation Meaning AcOH or HOAc acetic acid ACN or MeCN acetonitrile Bn benzyl BnBr benzyl bromide BnO or OBn benzyloxy Boc tert-butoxycarbonyl Boc₂O or (Boc)₂O di-tert-butyldicarbonate tBuXPhos-Pd-G3 [(2-di-tert-butylphosphino-2′,4′,6′- triisopropyl-1,1′-biphenyl)- 2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate Cbz benzyloxycarbonyl DCE dichloroethane DCM dichloromethane (CH₂Cl₂) DIBAL-H diisobutylaluminium hydride DIPEA N,N-diisopropylethylamine DMF dimethyl formamide DMA dimethylacetamide DMAP 4-dimethylaminopyridine DMB 2,4-dimethoxybenzyl DMSO dimethylsulfoxide EA or EtOAc ethyl acetate EtOH ethanol Et₂O diethylether HCl hydrochloric acid HPLC high performance liquid chromatography h/hr/hrs/min/s hour(s)(h, hr or hrs)/ minute(s)(min/mins)/second(s) K₂CO₃ potassium carbonate KOAc potassium acetate K₃PO₄ potassium phosphate LAH lithium aluminium hydride LC/MS, LCMS or LC-MS liquid chromatographic mass spectroscopy LDA lithium diisopropylamide LiHMDS lithium bis(trimethylsilyl)amide Me₄tBu-XPhos di-tert-butyl(2′,4′,6′-triisopropyl- 3,4,5,6-tetramethyl-[1,1′- biphenyl]-2-yl)phosphine MeI methyliodide MeOH methanol Me₂NH or NHMe₂ dimethylamine MS mass spectroscopy N₂ nitrogen Na₂SO₄ sodium sulfate NaBH(OAc)₃ sodium triacetoxyborohydride NaHMDS sodium bis(trimethylsilyl)amide NBS N-bromosuccinimide NH₄OH ammonium hydroxide NMO N-methylmorpholine-N-oxide NMP N-methyl-2-pyrrolidone n-BuLi n-butyl lithium NMR nuclear magnetic resonance Pd/C palladium on carbon Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium Pin pinacol psi pounds per square inch pressure S-Phos 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl TBDPSCl tert-butyldiphenylchlorosilane TBS tert-butyldimethylsilyl TBSCl tert-butyldimethylsilyl chloride t-BuOK potassium tert-butoxide TEA or NEt₃ triethylamine TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydro-2H-pyranyl THPO or OTHP tetrahydro-2H-pyran-2-yl-oxy TIPS-H or TIPSH triisopropylsilane TLC thin layer chromatography TMP 2,2,6,6-tetramethylpiperidinyl TMPMgCl-LiCl 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride TMSI trimethylsilyl iodide TMSOK potassium trimethylsilanolate

Example 1 (Compound 411) 2-{6-[8-Azabicyclo[3.2.1]oct-3-yl(methyl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol hydrochloride

Step 1: 3,6-Dibromopyridazine (133.7 mg, 0.56 mmol), tert-butyl (1R,5S)-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (85 mg, 0.28 mmol) and DIPEA (0.15 mL, 0.84 mmol) were mixed in 1 mL of ACN and heated to 100° C. for 1 h until LC-MS showed complete consumption of the starting material. The reaction mixture was concentrated and purified via column chromatography: eluting with gradient CH₂Cl₂/MeOH (0% to 30% MeOH), column: silica 4 g to afford tert-butyl (1S,5R)-3-[(6-bromopyridazin-3-yl)-methyl-amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (55 mg, 49.25% yield).

Step 2: tert-Butyl 3-[(6-bromopyridazin-3-yl)-methyl-amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (55 mg, 0.14 mmol), 4-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-tetrahydropyran-2-yl-pyrazole (68.82 mg, 0.17 mmol), Pd(dppf)Cl₂ (10.34 mg, 0.01 mmol), K₂CO₃ (57.98 mg, 0.42 mmol) were mixed in a Schlenk tube. The reaction was degassed with N₂ for 15 min and dioxane (2 mL) and water (0.5 mL) were added and the reaction was heated to 90° C. for 16 h. The reaction was cooled to room temperature, partitioned between EtOAc and water. The organic layers were dried over Na₂SO₄, concentrated under vacuum, purified via column chromatography: eluting with gradient CH₂Cl₂/EtOAc (0% to 80%), column: silica 4 g, to provide tert-butyl (1S,5R)-3-[[6-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]pyridazin-3-yl]-methyl-amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (52 mg, 62%) as a tan solid.

Step 3: To a solution of tert-butyl (1S,5R)-3-[[6-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]pyridazin-3-yl]-methyl-amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (52 mg, 0.086 mmol) in a 1 mL mixture of CH₂Cl₂ and 0.5 mL of MeOH was added HCl (4 mol/L) in 1,4-dioxane (0.06 mL). The reaction was stirred overnight. The precipitate was filtered, then dried under vacuum to provide 2-[6-[8-azabicyclo[3.2.1]octan-3-yl(methyl)amino]pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol; hydrochloride (15 mg, 42.25% yield) as a yellow solid.

LC-MS: 377 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ: 9.37-9.51 (m, 1H), 8.87-8.96 (m, 1H), 8.31 (d, J=9.8 Hz, 1H), 8.12 (s, 2H), 7.74 (d, J=8.2 Hz, 2H), 7.19-7.27 (m, 2H), 4.80-4.92 (m, 1H), 4.08-4.14 (m, 3H), 3.07 (s, 3H), 2.30 (td, J=12.6, 2.8 Hz, 2H), 1.99-2.15 (m, 4H), 1.74-1.87 (m, 2H)

Using the procedure described for Example 1 above, additional compounds described herein may be prepared by substituting the appropriate starting materials reagents, and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 412 LC-MS: 363 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 9.24-9.34 (m, 1H), 9.09- 9.21 (m, 1H), 8.30 (d, J = 9.8 Hz, 1H), 8.09 (s, 2H), 7.64-7.67 (m, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.25-7.27 (m, 1H), 7.24 (s, 1H), 5.42 (br s, 2H), 4.23-4.31 (m, 1H), 4.00- 4.13 (m, 2H), 2.17 (s, 4H), 1.97-2.02 (m, 2H), 1.94 (td, J = 12.6, 2.5 Hz, 2H) 413 LC-MS: 393 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 9.34-9.49 (m, 1H), 8.43- 8.56 (m, 1H), 8.30 (d, J = 9.8 Hz, 1H), 8.10 (s, 2H), 7.63 (s, 2H), 7.19-7.30 (m, 2H), 5.77 (br s, 2H), 4.41-4.62 (m, 1H), 2.08 (dd, J = 11.7, 2.8 Hz, 2H), 1.72 (td, J = 12.1, 2.8 Hz, 2H), 1.53 (s, 6H), 1.49 (s, 6H) 415 LC-MS: 364 [M + H]⁺. ¹H NMR (500 M Hz, methanol-d₄) δ: 8.61 (d, J = 9.5 Hz, 1H), 8.24 (s, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 9.5 Hz, 1H), 7.38 (dd, J = 8.2, 1.6 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 5.65 (spt, J = 5.7 Hz, 1H), 4.25 (dd, J = 3.6, 2.8 Hz, 2H), 4.17-4.32 (m, 2H), 2.24 (s, 4H), 2.11 (tt, J = 11.2, 2.8 Hz, 2H) (3 hydrogens corresponding to OH and NH unobserved) 433 LC-MS: 363 [M + H]⁺. ¹H NMR (500 M Hz, methanol-d₄) δ: 8.42 (d, J = 9.5 Hz, 1H), 8.34 (s, 2H), 7.80 (d, J = 9.8 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.40 (dd, J = 8.2, 2.5 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 4.18 (td, J = 6.9, 0.9 Hz, 1H), 4.11-4.16 (m, 2H), 2.42-2.52 (m, 4H), 2.32-2.35 (m, 1H), 2.28-2.32 (m, 1H), 2.15-2.25 (m, 2H), (4 hydrogens corresponding to OH and NH unobserved)

Example 2 (Compound 416) 5-(5-Methyl-1H-pyrazol-4-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol

Step 1: 3-Methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoromethanesulfonate (80 mg, 0.16 mmol), (tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (59 mg, 0.19 mmol), Pd(dppf)Cl₂ (7 mg, 0.01 mmol), K₂CO₃ (66 mg, 0.48 mmol) were mixed in a Schlenk tube. The reaction was degassed with N₂ for 15 min and dioxane (2 mL) and water (0.5 mL) were added and the reaction was heated to 90° C. for 16 h. The reaction was cooled to room temperature, partitioned between EtOAc and water. The organic layers were dried over Na₂SO₄, concentrated under vacuum, then purified via column chromatography: eluting with gradient CH₂Cl₂/MeOH (0% to 30% MeOH), column: silica 4 g to provide tert-butyl 4-(3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-3-methyl-1H-pyrazole-1-carboxylate (46 mg, 54%) as light brown solid.

Step 2: A solution of tert-butyl 4-(3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-3-methyl-1H-pyrazole-1-carboxylate (46 mg, 0.09 mmol) in 2 mL of dry CH₂Cl₂ was cooled in ice-water bath. Boron tribromide 1.0 M in CH₂Cl₂ (0.45 mL, 0.45 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with 2 mL of MeOH, stirred for 30 min, then concentrated and purified via column chromatography: eluting with gradient CH₂Cl₂/MeOH (2.5% NH₄OH) (0% to 30% MeOH/NH₄OH), column: silica 4 g, to provide tert-butyl 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(3-methyl-1H-pyrazol-4-yl)phenol (20 mg, 55%) as a yellow solid.

LC-MS: 421 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ: 13.74 (s, 1H), 12.63-12.71 (m, 1H), 8.20 (d, J=9.5 Hz, 1H), 8.03-8.04 (m, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.73-7.75 (m, 1H), 7.36 (d, J=9.5 Hz, 1H), 7.03-7.06 (m, 2H), 4.90-5.05 (m, 1H), 2.92 (s, 3H), 2.43 (s, 3H), 1.43-1.54 (m, 2H), 1.15-1.43 (m, 2H), 1.14 (s, 6H), 1.09 (s, 6H)

Using the procedure described for Example 2 above, additional compounds described herein may be prepared by substituting the appropriate starting materials reagents, and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 414 LC-MS: 408 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 13.84 (s, 1H), 8.10-8.29 (m, 2H), 7.92 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 9.8 Hz, 1H), 7.08-7.19 (m, 2H), 4.87-5.03 (m, 1H), 3.87 (s, 3H), 2.96 (s, 3H), 1.48-1.59 (m, 2H), 1.38-1.48 (m, 2H), 1.26 (s, 6H), 1.09 (s, 6H) 418 LC-MS: 422 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 12.89 (s, 1H), 12.29-12.48 (m, 1H), 8.41 (dd, J = 8.8, 0.9 Hz, 1H), 7.95 (dd, J = 7.9, 0.9 Hz, 1H), 7.37 (dd, J = 9.1, 1.3 Hz, 1H), 6.85-6.94 (m, 2H), 5.61-5.70 (m, 1H), 2.25 (br s., 6H), 2.09 (dd, J = 11.8, 3.9 Hz, 2H), 1.25-1.33 (m, 2H), 1.24 (s, 6H), 1.11 (s, 6H), (1 hydrogen corresponding to OH or NH unobserved) 451 LC-MS: 408 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 13.00 (s, 1H), 12.59-12.80 (m, 1H), 8.42 (d, J = 9.5 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 9.5 Hz, 1H), 7.03-7.18 (m, 2H), 5.55-5.78 (m, 1H), 2.39 (br s., 3H), 2.03-2.13 (m, 2H), 1.26-1.41 (m, 2H), 1.24 (s, 6H), 1.11 (s, 6H), (1 hydrogen corresponding to OH or NH unobserved)

Example 3 (Compound 419) 2-{6-[Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H-pyrazol-1-yl)phenol dihydrochloride

Step 1: 3-Methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoromethanesulfonate (335 mg, 0.67 mmol), 4-nitro-1H-pyrazole (340 mg, 4.5 mmol), Pd₂(dba)₃ (67 mg, 0.07 mmol), Me₄tBu-XPhos (35 mg, 0.07 mmol), K₃PO₄ (368 mg, 1.73 mmol) were mixed in a Schlenk tube. The reaction was degassed with N₂ for 15 min and dioxane (8 mL) was added and the reaction was heated to 90° C. for 16 h. The reaction was cooled to room temperature, filtered through celite, concentrated, purified via column chromatography: eluting with gradient CH₂Cl₂/MeOH (0% to 30% MeOH), column: silica 12 g, to provide 6-(2-methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (202 mg, 65%).

LC-MS: 466 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ: 9.81-9.85 (m, 1H), 8.61 (d, J=0.6 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.81 (d, J=9.8 Hz, 1H), 7.73 (d, J=1.9 Hz, 1H), 7.68 (dd, J=8.2, 2.2 Hz, 1H), 7.10-7.21 (m, 1H), 5.08-5.26 (m, 1H), 3.96 (s, 3H), 2.95 (s, 3H), 1.59-1.75 (m, 4H), 1.40 (s, 6H), 1.33, (s, 6H), (1 hydrogen corresponding to OH or NH unobserved)

Step 2: 6-(2-Methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (150 mg, 0.32 mmol), benzenethiol (33 μL, 0.32 mmol) and K₂CO₃ (44 mg, 0.32 mmol) were mixed in a microwave tube. The reaction was degassed with N₂ for 15 min and dry NMP (1.5 mL) was added. The reaction was heated in a Biotage microwave at 190° C. for 20 min, then diluted with 10 mL EtOAc, and washed with water and brine. The product was dried over Na₂SO₄, concentrated under vacuum, then purified via column chromatography: eluting with gradient CH₂Cl₂/MeOH (0% to 30% MeOH), column: silica 4 g, to provide 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(4-nitro-1H-pyrazol-1-yl)phenol (60 mg, 42%) as a brown solid.

LC-MS: 452 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ: 9.77 (s, 1H), 8.68 (d, J=9.8 Hz, 1H), 8.62 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 7.87-7.94 (m, 1H), 7.66 (dd, J=8.5, 2.6 Hz, 1H), 7.64 (d, J=2.6 Hz, 1H), 5.03-5.22 (m, 1H), 3.01 (s, 3H), 1.84-1.94 (m, 2H), 1.70-1.77 (m, 2H), 1.53 (s, 6H), 1.43 (s, 6H), (2 hydrogens corresponding to OH and NH unobserved)

Using the procedure described for Example 3 above, additional compounds described herein may be prepared by substituting the appropriate starting materials reagents, and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 417 LC-MS: 394 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 13.49 (br s, 1H), 8.49 (d, J = 9.8 Hz, 1H), 8.39 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.79-7.92 (m, 1H), 7.43 (d, J = 9.5 Hz, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.30 (dd, J = 8.5, 2.5 Hz, 1H), 7.12 (s, 1H), 5.61-5.71 (m, 1H), 2.09 (dd, J = 12.0, 3.8 Hz, 2H), 1.25-1.32 (m, 2H), 1.24 (s, 6H), 1.11 (s, 6H), (1 hydrogen corresponding to OH or NH unobserved) 421 LC-MS: 409 [M + H]⁺. ¹H NMR (500 M Hz, methanol-d₄) δ: 8.31 (d, J = 9.5 Hz, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.79 (d, J = 0.6 Hz, 1H), 7.44 (d, J = 0.9 Hz, 1H), 7.24-7.33 (m, 3H), 5.77 (tt, J = 11.2, 4.1 Hz, 1H), 2.28 (dd, J = 12.3, 4.2 Hz, 2H), 1.49 (t, J = 12.3 Hz, 2H), 1.42 (s, 6H), 1.30 (s, 6H), (4 hydrogens corresponding to OH and NH unobserved) 423 LC-MS: 439 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 9.71 (d, J = 0.6 Hz, 1H), 8.58 (d, J = 0.6 Hz, 1H), 8.47 (d, J = 9.5 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.59-7.64 (m, 2H), 7.44 (d, J = 9.5 Hz, 1H), 5.67-5.73 (m, 1H), 2.18-2.28 (m, 2H), 1.45-1.56 (m, 2H), 1.37 (s, 6H), 1.27 (s, 6H), ), (2 hydrogens corresponding to OH and NH unobserved)

Example 4 (Compound 424) 5-(1H-Pyrazol-4-yl)-2-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]phenol trihydrochloride

Step 1: 3-Bromo-6-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazine (100 mg, 0.24 mmol), (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (66 mg, 0.29 mmol), PddppfCl₂ (8 mg, 0.012 mmol), K₂CO₃ (99 mg, 0.72 mmol) were mixed in a Schlenk tube. The reaction was degassed with N₂ for 15 min and dioxane (2 mL) and water (0.5 mL) were added and the reaction was heated to 90° C. for 16 h. The reaction was cooled to room temperature, and partitioned between EtOAc and water. The organic layers were dried over Na₂SO₄, then concentrated under vacuum, and purified via column chromatography: eluting with gradient CH₂Cl₂/MeOH (0% to 20% MeOH), column: silica 4 g, to provide 5-(1H-pyrazol-4-yl)-2-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)phenol (102 mg, 82%) as an off-white solid.

Step 2: A solution of 5-(1H-pyrazol-4-yl)-2-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)phenol (102 mg, 0.196 mmol) in 2 mL of dry CH₂Cl₂ was cooled in ice-water bath. Boron tribromide 1.0 M in CH₂Cl₂(0.98 mL, 0.98 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with 2 mL of MeOH, stirred for 30 min, then concentrated and purified using preparative HPLC to provide 5-(1H-pyrazol-4-yl)-2-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)phenol (41 mg, 66%) as an off-white solid.

LC-MS: 320 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ: 9.19 (br S, 2H), 8.54 (d, J=9.6 Hz, 1H), 8.22, (d, J=9.6 Hz, 1H), 8.18 (s, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.25-7.29 (m, 2H), 6.92 (s, 1H), 3.85-3.92 (m, 2H), 3.38-3.41 (m, 2H), 2.88-2.98 (m, 2H), (1 hydrogen corresponding to OH or NH unobserved)

Using the procedure described for Example 4 above, additional compounds described herein may be prepared by substituting the appropriate starting materials reagents, and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 422 LC-MS: 334 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 11.06 (br s, 1H), 8.56 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 9.2 Hz, 1H), 8.20 (s, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.22-7.31 (m, 2H), 6.92 (s, 1H), 4.06-4.12 (m, 1H), 3.87-3.94 (m, 1H), 3.62-3.70 (m, 1H), 3.21-3.30 (m, 1H), 3.07-3.12 (m, 2H), 3.03 (s, 3H), (1 hydrogen corresponding to OH or NH unobserved) 425 LC-MS: 348 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 10.94 (br S, 1H), 8.56 (d, J = 9.6 Hz, 1H), 8.26 (d, J = 9.6 Hz, 1H), 8.19-8.23 (m, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.26-7.31 (m, 2H), 6.93 (s, 1H), 4.07-4.13 (m, 1H), 3.85-3.91 (m, 1H), 3.70-3.74 (m, 1H), 3.22-3.30 (m, 3H), 3.08-3.14 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H), (1 hydrogen corresponding to OH or NH unobserved) 429 LC-MS: 346 [M + H]⁺. ¹H NMR (500 M Hz, methanol-d₄) δ: 1.79-1.89 (m, 1H) 1.98- 2.11 (m, 1H) 2.11-2.33 (m, 2H) 2.65-2.80 (m, 1H) 3.09-3.21 (m, 1H) 4.02- 4.16 (m, 2H) 7.02-7.14 (m, 1H) 7.24 (s, 2 H) 7.85-7.97 (m, 1H) 8.04 (d, J = 9.46 Hz, 3H) 8.33 (d, J = 9.46 Hz, 1H)

Example 5 (Compound 427) 2-[6-(Piperidin-4-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride

Step 1: 3,6-Dibromopyridazine (500 mg, 2.1 mmol), 4-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (970 mg, 2.52 mmol), Pd(dppf)Cl₂ (77 mg, 0.11 mmol), K₂CO₃ (870 mg, 6.3 mmol) were mixed in a Schlenk tube. The reaction was degassed with N₂ for 15 min and dioxane (8 mL) and water (1 mL) were added and the reaction was heated to 90° C. for 16 h. The reaction was cooled to room temperature, partitioned between EtOAc and water. The organic layers were dried over Na₂SO₄, concentrated under vacuum, purified via column chromatography: eluting with gradient hexanes/EtOAc (0% to 40% EtOAc), column: silica 4 g, to provide 3-bromo-6-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazine (690 mg, 79%) as an off-white fluffy solid.

Step 2: 3-Bromo-6-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazine (50 mg, 0.12 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (36 mg, 0.18 mmol), potassium t-butoxide (41 mg, 0.36 mmol), tBuXPhos-Pd-G3 (10 mg, 0.012 mmol) were mixed in a Schlenk tube. The reaction was degassed with Ar then dry THF (2 mL) was added and the reaction was heated to 80° C. for 12 h. The reaction was cooled to room temperature, then partitioned between EtOAc and water. The organic layers were dried over Na₂SO₄, concentrated under vacuum, and purified via column chromatography: eluting with gradient CH₂Cl₂/MeOH (0% to 15% MeOH), column: silica 4 g, to provide tert-butyl 4-((6-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (45 mg, 70%) as a tan solid.

Step 3: A solution of 4-((6-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (45 mg, 0.084 mmol) in 2 mL of dry CH₂Cl₂ was cooled in an ice-water bath. Boron tribromide 1.0 M in CH₂Cl₂ (0.42 mL, 0.42 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with 2 mL of MeOH, stirred for 30 min, then concentrated and purified using preparative HPLC to provide 2-(6-(piperidin-4-ylamino)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (21 mg, 73%) as a yellowish solid.

LC-MS: 377 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ: 8.95 (s, 2H), 8.25 (d, J=9.6 Hz, 1H), 8.09 (s, 2H), 7.69 (d, J=8.8 Hz, 1H), 7.49-7.41 (m, 1H), 7.21-7.24 (m, 2H), 4.11-4.15 (m, 1H), 3.34-3.39 (m, 4H), 3.01-3.08 (m, 2H), 2.11-2.17 (m, 2H), 1.79 (q, J=9.2 Hz, 2H)

Using the procedure described for Example 5 above, additional compounds described herein may be prepared by substituting the appropriate starting materials reagents, and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 426 LC-MS: 351 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 9-22-9.28 (m, 2H), 8.34 (d, J = 9.6 Hz, 1H), 8.06-8.11 (m, 2H), 78.5-7.89 (m, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.20-7.27 (m, 2H), 4.67-4.75 (m, 2H), 3.35-3.39 (m, 2H), 3.07-3.09 (m, 2H), 3.05 (s, 3H), 2.21 (q, J = 10.2 Hz, 2H), 1.83-1.88 (m, 2H) 432 LC-MS: 338 [M + H]⁺. ¹H NMR (500 M Hz, methanol-d₄) δ: 8.72 (d, J = 9.6 Hz, 1H), 8.41-8.54 (m, 2H), 7.91-8.08 (m, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 5.51 (quint, J = 2.8 Hz, 1H), 3.30-3.46 (m, 2H), 3.28-3.31 (m, 2H), 2.33-2.38 (m, 2H), 2.25-2.32 (m, 2H), (3 hydrogens corresponding to OH and NH unobserved) 436 LC-MS: 366 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 9.17-9.30 (m, 1H), 8.81- 8.95 (m, 1H), 8.49 (d, J = 9.8 Hz, 1H), 8.17 (s, 2H), 7.94 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 9.8 Hz, 1H), 7.18-7.29 (m, 2H), 5.47 (spt, J = 5.7 Hz, 1H), 3.31-3.52 (m, 2H), 2.41 (dd, J = 12.9, 5.7 Hz, 2H), 1.68 (q, J = 12.0 Hz, 2H), 1.34 (d, J = 6.3 Hz, 6H), (1 hydrogen corresponding to OH or NH unobserved) 439 LC-MS: 363 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 9.07 (s, 2H), 8.28 (d, J = 10 Hz, 1H), 1.7 (s, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 9.6 Hz, 1H), 7.19-7.22 (m, 2H), 3.75-3.81 (m, 4H), 3.58-3.69 (m, 4H), 1.85-1.89 (m, 4H), (1 hydrogen corresponding to OH or NH unobserved) 459 LC-MS: 349 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 10.53 (s, 1H), 10.40 (s, 1H), 9.79 (br s, 1H), 9.67 (br s, 1H), 8.28 (d, J = 9.6 Hz, 1H), 8.06 (s, 2H), 7.65 (d, J = 9.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.21-7.25 (m, 1H), 4.53 (q, J = 14 Hz, 2H), 3.64 (d, J = 12.8 Hz, 1H), 3.52 (d, J = 12.8 Hz, 1H), 3.37-3.40 (m, 2H), 3.15-3.24 (m, 2H), 1.92-2.02 (m, 2H)

Example 6 (Compound 430) 6-[2,3-Difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride

Step 1: To a RBF, equipped with a N₂ inlet, were added: 6-bromo-N-methyl-N-(2,2,6,6-tetramethyl-4-piperidyl)pyridazin-3-amine (90 mg, 0.28 mmol),4-[2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-tetrahydropyran-2-yl-pyrazole (128.8 mg, 0.33 mmol), Pd(PPh₃)₄(31.8 mg, 0.03 mmol), Na₂CO₃ (87.43 mg, 0.83 mmol). The reaction was degassed with N₂ for 15 min then dioxane (8 mL) and water (2 mL) were added. The reaction was heated to 90° C. for 16 h, then cooled to room temperature, and partitioned between EtOAc and water. The organic layers were dried over Na₂SO₄, concentrated on a rotavap, and purified via column chromatography: eluting with gradient CH₂Cl₂/MeOH (0% to 30%), column: silica 4 g to provide 6-(2,3-Difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (88 mg, 63%) as a grey solid.

Step 2: 6-[2,3-Difluoro-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethyl-4-piperidyl)pyridazin-3-amine (88 mg, 0.17 mmol) was dissolved in MeOH (2 mL) and 4M HCl in dioxane (90 μL, 0.34 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min until LC-MS showed complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to provide 6-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride salt.

LC-MS: 427 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ: 9.21-9.33 (m, 1H), 8.27-8.43 (m, 1H), 8.20 (s, 2H), 8.01 (d, J=9.8 Hz, 1H), 7.60-7.79 (m, 3H), 5.01-5.14 (m, 1H), 3.05 (s, 3H), 2.10 (td, J=13.2, 1.6 Hz, 2H), 1.79 (dd, J=12.9, 4.1 Hz, 2H), 1.55 (s, 6H), 1.50 (s, 6H)

Using the procedure described for Example 6 above, additional compounds described herein may be prepared by substituting the appropriate starting materials reagents, and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 426 LC-MS: 427 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 9.22-9.38 (m, 1H), 8.33- 8.45 (m, 1H), 8.21 (d, J = 1.9 Hz, 2H), 7.97 (dd, J = 10.4, 2.8 Hz, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.81 (dd, J = 11.7, 6.6 Hz, 1H), 7.54-7.63 (m, 1H), 5.09-5.16 (m, 1H), 3.03 (s, 3H), 2.09 (t, J = 12.9 Hz, 2H), 1.78 (dd, J = 12.9, 3.8 Hz, 2H), 1.55 (s, 6H), 1.51 (s, 6H) 431 LC-MS: 414 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 9.24-9.35 (m, 1H), 8.43- 8.58 (m, 1H), 8.22 (d, J = 1.6 Hz, 2H), 8.06 (dd, J = 9.1, 1.9 Hz, 1H), 7.87 (dd, J = 12.1, 6.5 Hz, 1H), 7.83 (dd, J = 11.5, 6.5 Hz, 1H), 7.37 (d, J = 9.5 Hz, 1H), 5.77 (tt, J = 10.7, 4.1 Hz, 1H), 2.33 (dd, J = 13.1, 3.9 Hz, 2H), 1.84 (dd, J = 12.9, 11.3 Hz, 2H), 1.54 (s, 6H), 1.52 (s, 6H) 435 LC-MS: 378 [M + H]⁺. ¹H NMR (500 M Hz, methanol-d₄) δ: 8.57-8.58 (m, 1H), 8.55 (d, J = 5.0 Hz, 1H), 8.45 (s, 2H), 8.05-8.10 (m, 1H), 7.95-7.99 (m, 1H), 7.86 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H), 5.79 (tt, J = 10.4, 4.4 Hz, 1H), 2.53 (dd, J = 14.5, 4.5 Hz, 2H), 1.86-2.01 (m, 2H), 1.66 (s, 6H), 1.60 (s, 6H), (2 hydrogens corresponding to NH unobserved) 437 LC-MS: 396 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 9.28-9.44 (m, 1H), 8.47- 8.61 (m, 1H), 8.25 (s, 2H), 8.01 (dd, J = 9.3, 2.0 Hz, 1H), 7.92 (t, J = 8.2 Hz, 1H), 7.69 (dd, J = 12.8, 1.7 Hz, 1H), 7.65 (dd, J = 8.0, 1.7 Hz, 1H), 7.34 (d, J = 9.1 Hz, 1H), 5.76 (tt, J = 10.7, 4.1 Hz, 1H), 2.33 (dd, J = 13.2, 3.9 Hz, 2H), 1.85 (dd, J = 13.2, 10.1 Hz, 2H), 1.54 (s, 6H), 1.53 (s, 6H) 440 LC-MS: 359 [M + H]⁺. ¹H NMR (500 M Hz, methanol-d₄) δ: .06 (d, J = 10.1 Hz, 1H), 7.78 (dd, J = 9.5, 6.3 Hz, 1H), 7.32 (d, J = 9.8 Hz, 1H), 6.58-6.76 (m, 2H), 5.11 (tt, J = 12.0, 4.1 Hz, 1H), 3.02 (s, 3H), 1.73 (dd, J = 12.9, 3.5 Hz, 2H), 1.63 (t, J = 12.5 Hz, 2H), 1.43 (s, 6H), 1.27 (s, 6H), (1 hydrogen corresponding to NH unobserved) 441 LC-MS: 364 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 1.33 (d, J = 6.62 Hz, 6H) 1.65 (q, J = 12.40 Hz, 2H) 2.42 (d, J = 12.61 Hz, 2H) 3.38-3.50 (m, 2H) 5.48 (s, 1H) 6.51-6.63 (m, 1H) 7.42-7.57 (m, 3H) 7.80 (d, J = 1.58 Hz, 1H) 8.09 (d, J = 8.83 Hz, 1H) 8.50 (d, J = 9.46 Hz, 1H) 8.61 (d, J = 2.52 Hz, 1H) 8.76 (br s., 1H) 9.12 (br s., 1H) 13.18 (s, 1H) 442 LC-MS: 379 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 8.42 (s, 1H), 8.28 (dd, J = 1.6, 0.9 Hz, 1H), 8.03 (dd, J = 9.1, 1.6 Hz, 1H), 7.95 (s, 1H), 7.67 (d, J = 9.1 Hz, 1H), 7.14 (d, J = 9.1 Hz, 1H), 5.03-5.17 (m, 1H), 4.19 (s, 3H), 2.94 (s, 3H), 1.49-1.58 (m, 2H), 1.37-1.48 (m, 2H), 1.27 (s, 6H), 1.10 (s, 6H), (1 hydrogen corresponding to NH unobserved) 443 LC-MS: 366 [M + H]⁺. ¹H NMR (500 M Hz, methanol-d₄) δ: 8.35 (s, 1H), 8.31 (dd, J = 1.6, 0.9 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H), 7.99 (dd, J = 9.1, 1.9 Hz, 1H), 7.75 (dt, J = 9.1, 0.9 Hz, 1H), 7.21 (d, J = 9.5 Hz, 1H), 5.81 (tt, J = 11.2, 4.1 Hz, 1H), 4.27 (s, 3H), 2.28 (dd, J = 12.6, 4.1 Hz, 2H), 1.48 (t, J = 12.3 Hz, 2H), 1.41 (s, 6H), 1.30 (s, 6H), (1 hydrogen corresponding to NH unobserved) 445 LC-MS: 379 [M + H]⁺. ¹H NMR (500 M Hz, acetone-d₆) δ: 8.52 (dt, J = 7.0, 1.1 Hz, 1H), 8.13 (dt, J = 8.8, 1.3 Hz, 1H), 7.66 (d, J = 9.8 Hz, 1H), 7.28 (ddd, J = 9.0, 6.8, 1.3 Hz, 1H), 7.13 (d, J = 9.5 Hz, 1H), 6.89 (td, J = 6.9, 1.4 Hz, 1H), 5.22 (tt, J = 12.3, 3.5 Hz, 1H), 3.04 (s, 3H), 2.63 (s, 3H), 1.67 (dd, J = 12.3, 3.5 Hz, 2H), 1.56 (t, J = 12.3 Hz, 2H), 1.36 (s, 6H), 1.18 (s, 6H), (1 hydrogen corresponding to NH unobserved) 446 LC-MS: 352 [M + H]⁺. ¹H NMR (500 M Hz, acetone-d₆) δ: 9.14 (dd, J = 1.6, 0.9 Hz, 1H), 7.98 (dd, J = 9.5, 1.9 Hz, 1H), 7.94 (t, J = 0.9 Hz, 1H), 7.89 (d, J = 9.5 Hz, 1H), 7.63 (dt, J = 9.5, 0.8 Hz, 1H), 7.60 (d, J = 1.3 Hz, 1H), 7.14 (d, J = 9.5 Hz, 1H), 5.34 (tt, J = 12.6, 3.5 Hz, 1H), 1.67 (dd, J = 12.3, 3.8 Hz, 2H), 1.55 (t, J = 12.1 Hz, 2H), 1.36 (s, 6H), 1.17 (s, 6H), (1 hydrogen corresponding to NH unobserved) 447 LC-MS: 394 [M + H]⁺. ¹H NMR (500 M Hz, acetone-d₆) δ: 8.47 (d, J = 2.5 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 8.5, 2.2 Hz, 1H), 7.06 (d, J = 9.1 Hz, 1H), 6.57 (dd, J = 2.4, 1.7 Hz, 1H), 5.85 (tt, J = 11.3, 4.1 Hz, 1H), 2.21 (dd, J = 12.1, 3.9 Hz, 2H), 2.04-2.08 (m, 2H), 1.35 (s, 6H), 1.18 (s, 6H), (2 hydrogens corresponding to OH and NH unobserved) 452 LC-MS: 409 [M + H]⁺. ¹H NMR (500 M Hz, acetone-d₆) δ: 7.59 (dd, J = 8.5, 6.0 Hz, 1H), 7.46 (s, 2H), 7.31 (dd, J = 10.1, 2.5 Hz, 1H), 7.15 (td, J = 8.5, 2.5 Hz, 1H), 7.04 (d, J = 9.5 Hz, 1H), 6.91 (d, J = 9.5 Hz, 1H), 5.23 (tt, J = 12.3, 2.8 Hz, 1H), 3.00 (s, 3H), 1.65 (dd, J = 12.3, 3.5 Hz, 2H), 1.51 (t, J = 12.1 Hz, 2H), 1.33 (s, 6H), 1.15 (s, 6H), (2 hydrogens corresponding to NH unobserved) 455 LC-MS: 344 [M + H]⁺. ¹H NMR (500 M Hz, methanol-d₄) δ: 8.17 (d, J = 9.5 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 9.5 Hz, 1H), 6.44 (dd, J = 8.7, 2.4 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 5.71 (tt, J = 11.0, 3.8 Hz, 1H), 2.23 (dd, J = 12.6, 4.1 Hz, 2H), 1.40- 1.47 (m, 2H), 1.39 (s, 6H), 1.27 (s, 6H), (3 hydrogens corresponding to OH and NH unobserved) 456 LC-MS: 425 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 9.23-9.39 (m, 1H), 8.39- 8.52 (m, 1H), 8.26 (s, 2H), 8.00-8.08 (m, 1H), 7.93 (s, 1H), 7.81-7.85 (m, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 4.95-5.03 (m, 1H), 3.08 (s, 3H), 2.13 (t, J = 12.9 Hz, 2H), 1.81 (dd, J = 12.9, 3.5 Hz, 2H), 1.56 (s, 6H), 1.52 (s, 6H) 458 LC-MS: 414 [M + H]⁺. ¹H NMR (500 M Hz, DMSO-d₆) δ: 8.70-9.36 (m, 1H), 8.29 (s, 2H), 7.85 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 9.5 Hz, 1H), 7.33-7.39 (m, 1H), 5.59-5.68 (m, 1H), 2.24-2.33 (m, 2H), 1.72-1.82 (m, 2H), 1.50 (s, 6H), 1.48 (s, 6H), (2 hydrogens corresponding to NH unobserved)

Example 7 (Compound 434) 6-[2-Methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride

6-(2-Methoxy-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (6 mg) was dissolved in 1 mL of 4N HCl/dioxane and the resulting mixture was stirred at RT for 20 minutes. The mixture was evaporated and triturated with ether to provide 6-(2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 4 mg, 75%).

LC-MS: 422 [M+H]⁺. ¹H NMR (500 MHz, methanol-d₄) δ: 8.42-8.47 (m, 1H), 8.33-8.42 (m, 2H), 8.09-8.17 (m, 1H), 7.99-8.08 (m, 1H), 7.50-7.56 (m, 1H), 5.0 (m, 1H), 4.16 (s, 3H), 3.20 (s, 3H), 1.94-2.15 (m, 4H), 1.65 (s, 6H), 1.57 (s, 6H)

Example 8 (Compound 460) 3-{6-[Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-6-(H-pyrazol-4-yl)pyridin-2-ol hydrochloride

Step 1: 6-Chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (280 mg, 1.0 mmol) was dissolved in 10 mL, a mixture of dioxane and water (4:1). To the solution was added sodium carbonate (190 mg, 3 eq), (6-chloro-2-methoxypyridin-3-yl)boronic acid (190 mg, 1 eq) and Pd(Ph₃P)₄ (70 mg, 0.1 eq). The reaction mixture was stirred at 90° C. for 16 h, then applied to a column and purified using DCM/MeOH to yield (133 mg, 55%) 6-(6-chloro-2-methoxypyridin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine.

LC-MS: 390 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ: 8.25 (d, J=7.88 Hz, 1H), 7.83 (d, J=9.77 Hz, 1H), 7.24 (d, J=7.88 Hz, 1H), 7.11 (d, J=9.77 Hz, 1H), 5.00-5.24 (m, 1H), 3.93 (s, 3H), 2.87-2.96 (m, 3H), 1.40-1.57 (m, 4H), 1.21-1.29 (m, 7H), 1.10 (br s, 6H

Step 2: 6-(6-Chloro-2-methoxypyridin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (90 mg) was dissolved in a mixture of dioxane and water (4:1, 5 mL). To the solution was added sodium carbonate (100 mg, 3 eq), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (70 mg, 1.1 eq) and Pd(Ph₃P)₄ (27 mg, 0.1 eq). The reaction mixture was stirred at 90° C. for 16 h, then purified by column chromatography using DCM/MeOH to yield 80 mg (68%) of 6-(2-methoxy-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine.

Step 3: 6-(2-Methoxy-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (45 mg) was dissolved in 4 mL of 4N HCl/dioxane and the resulting mixture was heated for 2 hours at 60° C.F. The resulting mixture was evaporated and triturated with ether to provide 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-6-(1H-pyrazol-4-yl)pyridin-2-ol (24 mg, 61%).

LC-MS: 408 [M+H]+; ¹H NMR (500 MHz, methanol-d₄) δ: 8.62-8.69 (m, 1H), 8.55-8.61 (m, 1H), 8.39 (s, 2H), 7.95-8.06 (m, 1H), 7.04-7.14 (m, 1H), 5.02-5.24 (m, 1H), 3.18 (s, 3H), 2.03 (s, 4H), 1.67 (s, 6H), 1.57 (s, 6H)

Using the procedure described for Example 8 above, an additional compound described herein may be prepared by substituting the appropriate starting materials reagents, and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 461 LC-MS: 395 [M + H]⁺. ¹H NMR (500 M Hz, methanol-d₄) δ: 8.46 (d, J = 9.5 Hz, 1H), 8.33-8.42 (m, 1H), 8.29 (d, J = 7.6 Hz, 1H), 8.10-8.23 (m, 1H), 7.20 (d, J = 9.1 Hz, 1H), 6.86 (d, J = 7.3 Hz, 1H), 5.84 (tt, J = 10.4, 3.8 Hz, 1H), 2.49 (dd, J = 13.9, 4.1 Hz, 2H), 1.86 (dd, J = 13.9, 10.4 Hz, 2H), 1.65 (s, 6H), 1.56 (s, 6H), (3 hydrogens corresponding to OH and NH unobserved)

BIOLOGICAL EXAMPLES

The following in vitro biological examples demonstrate the usefulness of the compounds of the present description for treating Huntington's disease.

To describe in more detail and assist in understanding the present description, the following non-limiting biological examples are offered to more fully illustrate the scope of the description and are not to be construed as specifically limiting the scope thereof. Such variations of the present description that may be now known or later developed, which would be within the purview of one skilled in the art to ascertain, are considered to fall within the scope of the present description and as hereinafter claimed.

Example 1

Development and Validation of Meso Scale Discovery (MSD) Assay to Quantify Mutant and Total Huntingtin Protein (HTT)—Best Pair Analysis for Endogenous HTT Detection

To identify orally bioavailable small molecules useful for HTT reduction, high throughput ELISA methods to detect and measure both total HTT (wild-type and mutant)(tHTT) and mutant HTT (mHTT) in cells and tissues from HD patients and animal models are needed. The method described herein permits relatively high throughput protein measurement of tHTT and mHTT levels in cells and tissues from HD patients and in HD animal models. The ELISA method described herein enables screening of molecules for their ability to decrease the level of HTT and to identify and optimize small molecules for use in treating HD.

To determine the combination of antibodies that detect HTT (wild type and mutant) in a sensitive, high throughput format, multiple commercially available antibodies (Table 1) were screened in capture/detection combinations.

Protocol for Best Pair Analysis for Antibody Comparison in Detecting Total and Mutant HTT in Cells

-   1. Cells were cultured in a cell culture-compatible 96-well plate. -   2. The medium was removed and 50-100 L of lysis buffer per well     (composition described below) was added to cells to provide a “cell     lysate”. The plate was placed on a shaker at 4° C. for 30 minutes,     then stored at −20° C. -   3. A Capture Antibody Diluent was prepared by diluting the capture     antibody in PBS for standard plates as described in the plate     layout, then 30 μL of the Capture Antibody Diluent was added per     well. The plate was sealed and incubated at 4° C. overnight. -   4. The plate was washed 3× with 200 μL of Wash Buffer. Blocking     Buffer (150 μL per well) was added, then the plate was sealed and     incubated on a plate shaker for 3-4 hours at room temperature (RT). -   5. The Blocking Buffer was decanted and the plate was washed 3× with     200 μL of Wash Buffer. The cell lysate (25 μL per well) was then     added. The plate was sealed and incubated at 4° C. overnight. -   6. A First Detection Antibody Diluent was prepared by diluting a     first detection antibody for pairing in an Assay Antibody Diluent.     The plate was washed 3× with 200 μL of Wash Buffer, then 25 μL of     the First Detection Antibody Diluent was added per well. The plate     was sealed and incubated on a plate shaker for 1 hour at RT. -   7. A Second Detection Antibody Diluent was prepared by diluting a     second detection antibody for pairing in an Assay Antibody Diluent.     The plate was washed 3× with 200 μL of Wash Buffer, then 25 μL of     the Second Detection Antibody Diluent was added per well. The plate     was sealed and incubated on a plate shaker for 1 hour at RT. -   8. The Read Buffer was diluted 4×. The plate was washed 3× with 200     μL of Wash Buffer, then 150 μL of the Read Buffer was added per     well. The plate were read immediately following.

The various commercially available antibodies screened in the Best Pair Analysis, providing different capture/detection combinations are shown in Table 1. The capture/detection antibody pairs evaluated are shown in Table 2. The two antibody pairs that gave the maximum spread of values (higher signal to noise ratio) were selected for polyglutamine-expanded (mHTT) and total human HTT detection.

TABLE 1 Species ID Antibody Epitope monoclonal MAB2166 Huntingtin fragment from aa mouse 181-810 as a fusion protein monoclonal MAB2174 Huntingtin fusion protein 549-679, rat fused to Glutathione S-tranferase monoclonal MAB5374 GST fusion protein from the first 256 amino acids from human huntingtin with mouse the deletion of the polyglutamine tract goat sc-8767 Peptide mapping near the N-terminus of polyclonal Huntingtin of human origin (N18) monoclonal P1874 GST human Huntingtin (N-terminal mouse fragment of 171 amino acids containing 65Q) monoclonal MAB1574 Homopolymeric glutamine stretch mouse monoclonal #5656S Synthetic peptide corresponding rabbit to residues surrounding Pro1220 of human huntingtin protein monoclonal MW1 DRPLA-19Q mouse

TABLE 2 Signal to Pair HTT MSD ID Noise ratio Capture/Detection Total MAB2166/MAB2174 95 Capture/Detection Total MAB2166/sc-8767 6 Capture/Detection Total sc-8767/#5656 5 Capture/Detection Total MAB2166/#5656S 483 Capture/Detection Mutant MAB5374/#5656S 8 Capture/Detection Mutant MAB1574/#5656S 25 Capture/Detection Mutant P1874/#5656S 20 Capture/Detection Mutant MW1/#5656S 45

Characteristics for Best Pair capture/detection antibody pairs are those combinations that give minimum background and maximum signal. Such highly sensitive ELISA assays would be useful to detect HTT in the context of drug discovery for screening agents (small and large molecules and gene therapies) and for use in detecting HTT as a biomarker in clinical studies. Such capture/detection antibody pairs for quantifying total HTT are selected from MAB2166/MAB2174 and MAB2166/#5656S. Such capture/detection antibody pairs for quantifying mutant HTT are selected from MAB 1574/#5656S, P1874/#5656S and MW1/#5656S. The antibody pair for mHTT (MW1/#5656S) and the other for total HTT (MAB2166/#5656S) from this analysis were further optimized and validated to provide high-throughput assays that enabled HTT detection in patient fibroblasts and lymphocytes.

The Endogenous Huntingtin Protein assay used in Example 2 was developed using the Best Pair antibodies identified in Table 2, providing highly sensitive, high-throughput detection assays for polyglutamine-expanded (mHTT) and total human HTT in multiple cell systems. The platform used for the assay is the ELISA-based Meso Scale Discovery (MSD) electrochemiluminescence assay platform.

Example 2 Endogenous Huntingtin Protein Assay

Meso Scale Discovery (MSD) 96-well or 384-well plates were coated overnight at 4° C. with MW1 (expanded polyglutamine) or MAB2166 monoclonal antibody (for capture) at a concentration of 1 μg/mL in PBS (30 μL per well). Plates were then washed three times with 300 μL wash buffer (0.05% Tween-20 in PBS) and blocked (100 μL blocking buffer; 5% BSA in PBS) for 4-5 hours at room temperature with rotational shaking and then washed three times with wash buffer.

Samples (25 μL) were transferred to the antibody-coated MSD plate and incubated overnight at 4° C. After removal of the lysates, the plate was washed three times with wash buffer, and 25 μL of #5656S (Cell signaling; rabbit monoclonal) secondary antibody (diluted to 0.25 μg/mL in 0.05% Tween-20 in blocking buffer) was added to each well and incubated with shaking for 1 Hour at room temperature. Following incubation with the secondary antibody, the wells were rinsed with wash buffer after which 25 μL of goat anti-rabbit SULFO TAG secondary detection antibody (required aspect of the MSD system) (diluted to 0.25 μg/mL in 0.05% Tween-20 in blocking buffer) was added to each well and incubated with shaking for 1 hour at room temperature. After rinsing three times with wash buffer, 150 μL of read buffer T with surfactant (MSD) were added to each empty well, and the plate was imaged on a SI 6000 imager (MSD) according to manufacturers' instructions provided for 96- or 384-well plates. The resulting IC₅₀ values (μM) for compounds tested are shown in Table 3.

As shown in Table 3, test compounds described herein had the following IC₅₀ values, an IC₅₀ value between >3 μM and <9 μM is indicated by a single star (*), an IC₅₀ value between >1 μM and <3 μM is indicated by two stars (**), an IC₅₀ value between >0.5 μM and <1 μM is indicated by three stars (***), an IC₅₀ value between >0.1 μM and <0.5 μM is indicated by four stars (****) and an IC₅₀ value of <0.1 μM is indicated by five stars (*****).

TABLE 3 Cpd IC₅₀ Cpd IC₅₀ Cpd IC₅₀ 16 * 413 ***** 441 * 26 **** 414 ***** 442 * 31 *** 415 ***** 443 * 460 * 416 ***** 444 * 39 * 417 ***** 445 * 44 ***** 418 ***** 446 * 46 ***** 419 ***** 447 * 47 **** 420 ***** 448 * 48 ***** 421 ***** 449 * 51 ***** 422 ***** 450 * 63 ***** 423 ***** 451 * 64 ***** 424 **** 451 * 170 ***** 425 **** 452 * 176 ***** 426 **** 454 * 200 ***** 427 **** 455 * 207 **** 428 **** 456 * 212 ***** 429 **** 456 * 218 ***** 430 **** 456 * 258 **** 431 **** 457 * 307 **** 432 **** 458 * 315 ***** 433 **** 459 * 318 ***** 434 *** 460 * 348 ***** 435 *** 461 * 350 ***** 436 *** 462 * 352 **** 437 ** 463 * 393 ***** 438 ** 464 * 411 ***** 439 ** 465 * 412 ***** 440 *

Without regard to whether a document cited herein was specifically and individually indicated as being incorporated by reference, all documents referred to herein are incorporated by reference into the present application for any and all purposes to the same extent as if each individual reference was fully set forth herein.

Having now fully described the subject matter of the claims, it will be understood by those having ordinary skill in the art that the same can be performed within a wide range of equivalents without affecting the scope of the subject matter or embodiments described herein. It is intended that the appended claims be interpreted to include all such equivalents. 

1-3. (canceled)
 4. A compound selected from a compound of Formula (Ia11), Formula (Ia15), Formula (Ia18) or Formula (Ib1):

or a form thereof, wherein (when present), X is selected from O, NR₅, or a bond; A is selected from phenyl, thiophenyl, indazolyl, pyridinyl, pyrimidinyl or phenoxy, wherein phenyl and phenoxy are each optionally substituted with 1, 2 or 3 substituents each selected from R_(1a), wherein thiophenyl, indazolyl, pyridinyl, pyrimidinyl are each optionally substituted with 1 or 2 substituents each selected from R_(1a), B is selected from 1H-pyrazolyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, 2,6-diazaspiro[3.4]octyl or 2,7-diazaspiro[3.5]nonyl, each optionally substituted with 1 or 2 substituents each selected from R_(4a); R_(1a) is selected from halogen, hydroxyl, C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkoxy, or heteroaryl, wherein heteroaryl is a saturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S optionally substituted with 1 or 2 substituents each selected from R_(3a); R_(3a) is selected from nitro or C₁₋₄alkyl; and, R_(4a) is C₁₋₄alkyl; R_(5a) is hydrogen, C₁₋₄alkyl, or hydroxyl-C₁₋₄alkyl; wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.
 5. The compound of claim 4 wherein (when present): R_(1a) is selected from fluoro, chloro, hydroxyl, methyl, difluoromethyl, amino, methoxy or 1H-pyrazolyl or 1H-imidazol-1-yl, wherein 1H-pyrazolyl is optionally substituted with 1 or 2 substituents each selected from R_(3a); R_(3a) is selected from nitro or methyl or amino; and, R_(4a) is methyl or ethyl; R_(5a) is hydrogen or methyl; wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.
 6. (canceled)
 7. The compound of claim 4, wherein the compound is selected from the group consisting of: 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl(methyl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol 2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol 5-(1-methyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol 2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 5-(5-methyl-1H-pyrazol-4-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol 5-(1H-imidazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol 5-(5-methyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H-pyrazol-1-yl)phenol 6-[2-methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 5-(4-amino-1H-pyrazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol 2-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 5-(4-nitro-1H-pyrazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol 5-(1H-pyrazol-4-yl)-2-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]phenol 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 2-{6-[methyl(piperidin-4-yl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol 2-[6-(piperidin-4-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 2-[6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 2-[6-(piperidin-4-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol 6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 3-[4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol 3-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 3-[4-(1-methyl-1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 2-[6-(2,7-diazaspiro[3.5]non-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 3-fluoro-4-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-1-yl)phenol N-methyl-6-(2-methyl-2H-indazol-5-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 2-methyl-5-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}-2H-indazole 3-(4-chloro-2-methoxyphenyl)-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine N-methyl-6-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 6-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}imidazo[1,2-a]pyridine 3-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 3-[5-(1-methyl-1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol 6-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 3-methoxy-4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol 3-[2-methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}benzene-1,3-diol 6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 2-(1H-pyrazol-4-yl)-4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}pyrimidin-5-amine 3-[2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 2-[6-(2,6-diazaspiro[3.4]oct-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 3-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-6-(1H-pyrazol-4-yl)pyridin-2-ol 6-(1H-pyrazol-4-yl)-3-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}pyridin-2-ol N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2-yl}piperidin-4-amine N,2,2,6,6-pentamethyl-N-{5-[4-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2-yl}piperidin-4-amine 3-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine and 6-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine; wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.
 8. (canceled)
 9. The compound of claim 7, wherein the compound is a compound salt selected from the group consisting of: 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl(methyl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol hydrochloride 2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol hydrochloride 2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H-pyrazol-1-yl)phenol dihydrochloride 2-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol trihydrochloride 5-(1H-pyrazol-4-yl)-2-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]phenol trihydrochloride 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol trihydrochloride 2-{6-[methyl(piperidin-4-yl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 2-[6-(piperidin-4-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine tetrahydrochloride 2-[6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine trihydrochloride 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol hydrochloride 6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol trihydrochloride 3-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine hydrochloride 2-[6-(2,7-diazaspiro[3.5]non-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine hydrochloride 3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine hydrochloride 6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine trihydrochloride 3-[2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine trihydrochloride 3-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-6-(1H-pyrazol-4-yl)pyridin-2-ol hydrochloride N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2-yl}piperidin-4-amine hydrochloride N,2,2,6,6-pentamethyl-N-{5-[4-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2-yl}piperidin-4-amine hydrochloride 3-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine hydrochloride and 6-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride; wherein a form of the compound salt is selected from the group consisting of a hydrate, solvate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.
 10. An assay for detecting HTT (Huntingtin protein) using capture/detection antibody pairs, wherein HTT is total HTT and the capture/detection antibody pairs are selected from MAB2166/MAB2174 and MAB2166/#5656S; and, wherein HTT is mutant HTT and the capture/detection antibody pairs are selected from MAB1574/#5656S, P1874/#5656S and MW1/#5656S.
 11. The assay of claim 10, wherein HTT is total HTT and the capture/detection antibody pair is MAB2166/#5656S; and, wherein HTT is mutant HTT and the capture/detection antibody pair is MW1/#5656S. 12-18. (canceled) 